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Bian L, Hu B, Li F, Gu Y, Hu C, Chen Y, Deng B, Fang H, Zhu X, Chen Y, Fu X, Wang T, She Q, Zhu M, Jiang Y, Dai J, Xu H, Ma H, Xu Z, Hu Z, Shen H, Ding Y, Yan C, Jin G. Single-cell eQTL mapping reveals cell-type-specific genes associated with the risk of gastric cancer. CELL GENOMICS 2025:100812. [PMID: 40112817 DOI: 10.1016/j.xgen.2025.100812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 01/05/2025] [Accepted: 02/18/2025] [Indexed: 03/22/2025]
Abstract
Most expression quantitative trait locus (eQTL) analyses have been conducted in heterogeneous gastric tissues, limiting understanding of cell-type-specific regulatory mechanisms. Here, we employed a pooled multiplexing strategy to profile 399,683 gastric cells from 203 Chinese individuals using single-cell RNA sequencing (scRNA-seq). We identified 19 distinct gastric cell types and performed eQTL analyses, uncovering 8,498 independent eQTLs, with a considerable fraction (81%, 6,909/8,498) exhibiting cell-type-specific effects. Integration of these eQTLs with genome-wide association studies for gastric cancer (GC) revealed four co-localization signals in specific cell types. Genetically predicted cell-type-specific gene expression identified 15 genes associated with GC risk, including the upregulation of MUC1 exclusively in parietal cells, linked to decreased GC risk. Our findings highlight substantial heterogeneity in the genetic regulation of gene expression across gastric cell types and provide critical cell-type-specific annotations of genetic variants associated with GC risk, offering new molecular insights underlying GC.
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Affiliation(s)
- Lijun Bian
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi 214023, China
| | - Beiping Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Fengyuan Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yuanliang Gu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Caihong Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Yuheng Chen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Bin Deng
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China
| | - Haisheng Fang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xia Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Yan Chen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Xiangjin Fu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Tianpei Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Qiang She
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China
| | - Meng Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Yue Jiang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Juncheng Dai
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hongxia Ma
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhibin Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China
| | - Hongbing Shen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China; Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yanbing Ding
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
| | - Caiwang Yan
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi 214023, China; Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China; Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China.
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Fan Z, Hao J, He F, Jiang H, Wang J, Li M, Li X, Chen R, Wei W. Novel DNA methylation markers for early detection of gastric cardia adenocarcinoma and esophageal squamous cell carcinoma. SCIENCE CHINA. LIFE SCIENCES 2024; 67:2701-2712. [PMID: 39235559 DOI: 10.1007/s11427-024-2642-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 05/29/2024] [Indexed: 09/06/2024]
Abstract
Gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) present significant health challenges in China, often diagnosed at advanced stages with poor prognoses. However, effective biomarkers for early detection remain elusive. This study aimed to integrate methylome and transcriptome data to identify DNA methylation markers for the early detection of GCA and ESCC. In the discovery stage, we conducted Infinium MethylationEPIC array analysis on 36 paired GCA and non-tumor adjacent tissues (NAT), identifying differentially methylated CpG sites (DMCs) between GCA/ESCC and NAT through combined analyses of in-house and publicly available data. In the validation stage, targeted pyrosequencing and quantitative real-time RT-PCR were performed on paired tumor and NAT samples from 50 GCA and 50 ESCC patients. In the application stage, an independent set of 438 samples, including GCA, ESCC, high- and low-grade dysplasia (HGD/LGD), and normal controls, was tested for selected DMCs using pyrosequencing. Our analysis validated three GCA-specific, two ESCC-specific, and one tumor-shared DMCs, exhibiting significant hypermethylation and decreased expression of target genes in tumor samples compared with NAT. Leveraging these DMCs, we developed a GCA-specific 4-marker panel (cg27284428, cg11798358, cg07880787, and cg00585116) with an area under the receiver operating characteristic curve (AUC) of 0.917, effectively distinguishing between cardia HGD/GCA patients and cardia LGD/normal controls. Similarly, an ESCC-specific 3-marker panel (cg14633892, cg04415798, and cg00585116) achieved an AUC of 0.865 in distinguishing esophageal HGD/ESCC cases. Furthermore, integrating cg00585116, age, and alcohol consumption yielded a tumor-shared logistic model with good discrimination for two cancer/HGD (AUC, 0.767; 95% confidence interval, 0.720-0.813). The mean AUC of the model after 5-fold cross-validation was 0.764. In summary, our study identifies novel DNA methylation markers capable of accurately distinguishing GCA/ESCC and HGD from LGD and normal controls. These findings offer promising prospects for targeted DNA methylation assays in future minimally invasive cancer screening methods.
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Affiliation(s)
- Zhiyuan Fan
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jiajie Hao
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Feifan He
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hao Jiang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Jinwu Wang
- Department of Pathology, Linzhou Cancer Hospital, Linzhou, 456550, China
| | - Minjuan Li
- Department of Orthopedic Surgery, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China
| | - Xinqing Li
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ru Chen
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wenqiang Wei
- Office of National Central Cancer Registry, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
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Aznar-Gimeno R, García-González MA, Muñoz-Sierra R, Carrera-Lasfuentes P, Rodrigálvarez-Chamarro MDLV, González-Muñoz C, Meléndez-Estrada E, Lanas Á, Del Hoyo-Alonso R. GastricAITool: A Clinical Decision Support Tool for the Diagnosis and Prognosis of Gastric Cancer. Biomedicines 2024; 12:2162. [PMID: 39335675 PMCID: PMC11429470 DOI: 10.3390/biomedicines12092162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/10/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND/OBJECTIVE Gastric cancer (GC) is a complex disease representing a significant global health concern. Advanced tools for the early diagnosis and prediction of adverse outcomes are crucial. In this context, artificial intelligence (AI) plays a fundamental role. The aim of this work was to develop a diagnostic and prognostic tool for GC, providing support to clinicians in critical decision-making and enabling personalised strategies. METHODS Different machine learning and deep learning techniques were explored to build diagnostic and prognostic models, ensuring model interpretability and transparency through explainable AI methods. These models were developed and cross-validated using data from 590 Spanish Caucasian patients with primary GC and 633 cancer-free individuals. Up to 261 variables were analysed, including demographic, environmental, clinical, tumoral, and genetic data. Variables such as Helicobacter pylori infection, tobacco use, family history of GC, TNM staging, metastasis, tumour location, treatment received, gender, age, and genetic factors (single nucleotide polymorphisms) were selected as inputs due to their association with the risk and progression of the disease. RESULTS The XGBoost algorithm (version 1.7.4) achieved the best performance for diagnosis, with an AUC value of 0.68 using 5-fold cross-validation. As for prognosis, the Random Survival Forest algorithm achieved a C-index of 0.77. Of interest, the incorporation of genetic data into the clinical-demographics models significantly increased discriminatory ability in both diagnostic and prognostic models. CONCLUSIONS This article presents GastricAITool, a simple and intuitive decision support tool for the diagnosis and prognosis of GC.
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Affiliation(s)
- Rocío Aznar-Gimeno
- Department of Big Data and Cognitive Systems, Instituto Tecnológico de Aragón, ITA, María de Luna 7-8, 50018 Zaragoza, Spain
| | - María Asunción García-González
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain
- Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - Rubén Muñoz-Sierra
- Department of Big Data and Cognitive Systems, Instituto Tecnológico de Aragón, ITA, María de Luna 7-8, 50018 Zaragoza, Spain
| | - Patricia Carrera-Lasfuentes
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain
- Facultad de Ciencias de la Salud, Universidad San Jorge, 50830 Zaragoza, Spain
| | | | - Carlos González-Muñoz
- Department of Big Data and Cognitive Systems, Instituto Tecnológico de Aragón, ITA, María de Luna 7-8, 50018 Zaragoza, Spain
| | - Enrique Meléndez-Estrada
- Department of Big Data and Cognitive Systems, Instituto Tecnológico de Aragón, ITA, María de Luna 7-8, 50018 Zaragoza, Spain
| | - Ángel Lanas
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009 Zaragoza, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
- School of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Rafael Del Hoyo-Alonso
- Department of Big Data and Cognitive Systems, Instituto Tecnológico de Aragón, ITA, María de Luna 7-8, 50018 Zaragoza, Spain
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Waldron R, Rodriguez MDLAB, Williams JM, Ning Z, Ahmed A, Lindsay A, Moore T. JRK binds satellite III DNA and is necessary for the heat shock response. Cell Biol Int 2024; 48:1212-1222. [PMID: 38946594 DOI: 10.1002/cbin.12216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 04/19/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024]
Abstract
JRK is a DNA-binding protein of the pogo superfamily of transposons, which includes the well-known centromere binding protein B (CENP-B). Jrk null mice exhibit epilepsy, and growth and reproductive disorders, consistent with its relatively high expression in the brain and reproductive tissues. Human JRK DNA variants and gene expression levels are implicated in cancers and neuropsychiatric disorders. JRK protein modulates β-catenin-TCF activity but little is known of its cellular functions. Based on its homology to CENP-B, we determined whether JRK binds centromeric or other satellite DNAs. We show that human JRK binds satellite III DNA, which is abundant at the chromosome 9q12 juxtacentromeric region and on Yq12, both sites of nuclear stress body assembly. Human JRK-GFP overexpressed in HeLa cells strongly localises to 9q12. Using an anti-JRK antiserum we show that endogenous JRK co-localises with a subset of centromeres in non-stressed cells, and with heat shock factor 1 following heat shock. Knockdown of JRK in HeLa cells proportionately reduces heat shock protein gene expression in heat-shocked cells. A role for JRK in regulating the heat shock response is consistent with the mouse Jrk null phenotype and suggests that human JRK may act as a modifier of diseases with a cellular stress component.
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Affiliation(s)
- Rosalie Waldron
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | | | - John M Williams
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Zhenfei Ning
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Abrar Ahmed
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Andrew Lindsay
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Tom Moore
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
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Gnanapragasam A, Kirbizakis E, Li A, White KH, Mortenson KL, Cavalcante de Moura J, Jawhar W, Yan Y, Falter R, Russett C, Giannias B, Camilleri-Broët S, Bertos N, Cools-Lartigue J, Garzia L, Sangwan V, Ferri L, Zhang X, Bailey SD. HiChIP-Based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 That Confers Genetic Susceptibility to Gastroesophageal Cancer. Cancer Res 2024; 84:2377-2389. [PMID: 38748784 PMCID: PMC11247317 DOI: 10.1158/0008-5472.can-23-2397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 02/01/2024] [Accepted: 05/08/2024] [Indexed: 07/16/2024]
Abstract
Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNV) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and genes they modulate could help improve GEC prevention and treatment. Herein, we used HiChIP against histone 3 lysine 27 acetylation (H3K27ac) to simultaneously annotate active promoters and enhancers, identify the interactions between them, and detect nucleosome-free regions (NFR) harboring potential causal SNVs in a single assay. The application of H3K27ac HiChIP in GEC relevant models identified 61 potential functional SNVs that reside in NFRs and interact with 49 genes at 17 loci. The approach led to a 67% reduction in the number of SNVs in linkage disequilibrium at these 17 loci, and at 7 loci, a single putative causal SNV was identified. One SNV, rs147518036, located within the promoter of the UDP-glucuronate decarboxylase 1 (UXS1) gene, seemed to underlie the GEC risk association captured by the rs75460256 index SNV. The rs147518036 SNV creates a GABPA DNA recognition motif, resulting in increased promoter activity, and CRISPR-mediated inhibition of the UXS1 promoter reduced the viability of the GEC cells. These findings provide a framework that simplifies the identification of potentially functional regulatory SNVs and target genes underlying risk-associated loci. In addition, the study implicates increased expression of the enzyme UXS1 and activation of its metabolic pathway as a predisposition to gastric cancer, which highlights potential therapeutic avenues to treat this disease. Significance: Epigenomic footprinting using a histone posttranslational modification targeted 3D genomics methodology elucidates functional noncoding sequence variants and their target genes at cancer risk loci.
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Affiliation(s)
- Ansley Gnanapragasam
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Human Genetics, McGill University, Montreal, Canada
| | - Eftyhios Kirbizakis
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Human Genetics, McGill University, Montreal, Canada
| | - Anna Li
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
| | - Kyle H White
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Pathology, McGill University, Montreal, Canada
| | | | - Juliana Cavalcante de Moura
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
| | - Wajih Jawhar
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Surgery, McGill University, Montreal, Canada
| | - Yifei Yan
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
| | - Reilly Falter
- Department of Experimental Medicine, McGill University, Montreal, Canada
| | - Colleen Russett
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Human Genetics, McGill University, Montreal, Canada
| | - Betty Giannias
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
| | - Sophie Camilleri-Broët
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Nicholas Bertos
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
| | - Jonathan Cools-Lartigue
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Pathology, McGill University, Montreal, Canada
| | - Livia Garzia
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Human Genetics, McGill University, Montreal, Canada
- Department of Surgery, McGill University, Montreal, Canada
- Department of Pathology, McGill University, Montreal, Canada
| | - Veena Sangwan
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Pathology, McGill University, Montreal, Canada
| | - Lorenzo Ferri
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Pathology, McGill University, Montreal, Canada
| | - Xiaoyang Zhang
- Department of Experimental Medicine, McGill University, Montreal, Canada
| | - Swneke D Bailey
- The Cancer Research Program, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Canada
- Department of Human Genetics, McGill University, Montreal, Canada
- Department of Surgery, McGill University, Montreal, Canada
- Department of Pathology, McGill University, Montreal, Canada
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Zhu F, Yang X, Ouyang L, Man T, Chao J, Deng S, Zhu D, Wan Y. DNA Framework-Based Programmable Atom-Like Nanoparticles for Non-Coding RNA Recognition and Differentiation of Cancer Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400492. [PMID: 38569466 PMCID: PMC11187905 DOI: 10.1002/advs.202400492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/27/2024] [Indexed: 04/05/2024]
Abstract
The cooperative diagnosis of non-coding RNAs (ncRNAs) can accurately reflect the state of cell differentiation and classification, laying the foundation of precision medicine. However, there are still challenges in simultaneous analyses of multiple ncRNAs and the integration of biomarker data for cell typing. In this study, DNA framework-based programmable atom-like nanoparticles (PANs) are designed to develop molecular classifiers for intra-cellular imaging of multiple ncRNAs associated with cell differentiation. The PANs-based molecular classifier facilitates signal amplification through the catalytic hairpin assembly. The interaction between PAN reporters and ncRNAs enables high-fidelity conversion of ncRNAs expression level into binding events, and the assessment of in situ ncRNAs levels via measurement of the fluorescent signal changes of PAN reporters. Compared to non-amplified methods, the detection limits of PANs are reduced by four orders of magnitude. Using human gastric cancer cell lines as a model system, the PANs-based molecular classifier demonstrates its capacity to measure multiple ncRNAs in living cells and assesses the degree of cell differentiation. This approach can serve as a universal strategy for the classification of cancer cells during malignant transformation and tumor progression.
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Affiliation(s)
- Fulin Zhu
- School of Mechanical EngineeringNanjing University of Science and Technology200 Xiaolingwei StreetNanjing210094China
| | - Xinyu Yang
- School of Mechanical EngineeringNanjing University of Science and Technology200 Xiaolingwei StreetNanjing210094China
| | - Lilin Ouyang
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for BiosensorsInstitute of Advanced Materials (IAM)Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM)Nanjing University of Posts and Telecommunications9 Wenyuan RoadNanjing210023China
| | - Tiantian Man
- School of Mechanical EngineeringNanjing University of Science and Technology200 Xiaolingwei StreetNanjing210094China
| | - Jie Chao
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for BiosensorsInstitute of Advanced Materials (IAM)Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM)Nanjing University of Posts and Telecommunications9 Wenyuan RoadNanjing210023China
| | - Shengyuan Deng
- School of Environmental and Biological EngineeringNanjing University of Science and Technology200 Xiaolingwei StreetNanjing210094China
| | - Dan Zhu
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for BiosensorsInstitute of Advanced Materials (IAM)Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM)Nanjing University of Posts and Telecommunications9 Wenyuan RoadNanjing210023China
| | - Ying Wan
- School of Mechanical EngineeringNanjing University of Science and Technology200 Xiaolingwei StreetNanjing210094China
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Xu HM, Han Y, Liu ZC, Yin ZY, Wang MY, Yu C, Ma JL, Sun D, Liu WD, Zhang Y, Zhou T, Zhang JY, Pei P, Yang L, Millwood IY, Walters RG, Chen Y, Du H, Chen Z, You WC, Li L, Pan KF, Lv J, Li WQ. Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer. JAMA Netw Open 2024; 7:e2413708. [PMID: 38809553 PMCID: PMC11137637 DOI: 10.1001/jamanetworkopen.2024.13708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/25/2024] [Indexed: 05/30/2024] Open
Abstract
Importance Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures H pylori treatment and nutrition supplementation. Main Outcomes and Measures Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.
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Affiliation(s)
- Heng-Min Xu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yuting Han
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zong-Chao Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhou-Yi Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Meng-Yuan Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Canqing Yu
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Jun-Ling Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Dianjianyi Sun
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Wei-Dong Liu
- Linqu Public Health Bureau, Linqu, Shandong, China
| | - Yang Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Tong Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jing-Ying Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Pei Pei
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Ling Yang
- Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, United Kingdom
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Iona Y. Millwood
- Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, United Kingdom
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Robin G. Walters
- Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, United Kingdom
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Yiping Chen
- Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, United Kingdom
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Huaidong Du
- Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, United Kingdom
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Zhengming Chen
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Wei-Cheng You
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Liming Li
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Kai-Feng Pan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jun Lv
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Wen-Qing Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
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8
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Nayerpour Dizaj T, Doustmihan A, Sadeghzadeh Oskouei B, Akbari M, Jaymand M, Mazloomi M, Jahanban-Esfahlan R. Significance of PSCA as a novel prognostic marker and therapeutic target for cancer. Cancer Cell Int 2024; 24:135. [PMID: 38627732 PMCID: PMC11020972 DOI: 10.1186/s12935-024-03320-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 03/30/2024] [Indexed: 04/20/2024] Open
Abstract
One of the contributing factors in the diagnosis and treatment of most cancers is the identification of their surface antigens. Cancer tissues or cells have their specific antigens. Some antigens that are present in many cancers elicit different functions. One of these antigens is the prostate stem cell antigen (PSCA) antigen, which was first identified in the prostate. PSCA is a cell surface protein that has different functions in different tissues. It can play an inhibitory role in cell proliferation as well as a tumor-inducing role. PSCA has several genetic variants involved in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship with clinical features can provide more information on diagnosis and treatment of patients with cancers. Most studies on the PSCA have focused on prostate cancer. While it is also expressed in other cancers, little attention has been paid to its role as a valuable diagnostic, prognostic, and therapeutic tool in other cancers. PSCA has several genetic variants that seem to play a significant role in cancer susceptibility in some tissues, so identifying the characteristics of this antigen and its relationship and variants with clinical features can be beneficial in concomitant cancer therapy and diagnosis, as theranostic tools. In this study, we will review the alteration of the PSCA expression and its polymorphisms and evaluate its clinical and theranostics significance in various cancers.
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Affiliation(s)
- Tina Nayerpour Dizaj
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolfazl Doustmihan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behnaz Sadeghzadeh Oskouei
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - MirAhmad Mazloomi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Jahanban-Esfahlan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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9
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Zhang Y, Gao Y, Li F, Qi Q, Li Q, Gu Y, Zheng Z, Hu B, Wang T, Zhang E, Xu H, Liu L, Tian T, Jin G, Yan C. Long non-coding RNA NRAV in the 12q24.31 risk locus drives gastric cancer development through glucose metabolism reprogramming. Carcinogenesis 2024; 45:23-34. [PMID: 37950445 DOI: 10.1093/carcin/bgad080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 10/24/2023] [Accepted: 11/08/2023] [Indexed: 11/12/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) serve as vital candidates to mediate cancer risk. Here, we aimed to identify the risk single-nucleotide polymorphisms (SNPs)-induced lncRNAs and to investigate their roles in gastric cancer (GC) development. Through integrating the differential expression analysis of lncRNAs in GC tissues and expression quantitative trait loci analysis in normal stomach tissues and GC tissues, as well as genetic association analysis based on GC genome-wide association studies and an independent validation study, we identified four lncRNA-related SNPs consistently associated with GC risk, including SNHG7 [odds ratio (OR) = 1.16, 95% confidence interval (CI): 1.09-1.23], NRAV (OR = 1.11, 95% CI: 1.05-1.17), LINC01082 (OR = 1.16, 95% CI: 1.08-1.22) and FENDRR (OR = 1.16, 95% CI: 1.07-1.25). We further found that a functional SNP rs6489786 at 12q24.31 increases binding of MEOX1 or MEOX2 at a distal enhancer and results in up-regulation of NRAV. The functional assays revealed that NRAV accelerates GC cell proliferation while inhibits GC cell apoptosis. Mechanistically, NRAV decreases the expression of key subunit genes through the electron transport chain, thereby driving the glucose metabolism reprogramming from aerobic respiration to glycolysis. These findings suggest that regulating lncRNA expression is a crucial mechanism for risk-associated variants in promoting GC development.
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Affiliation(s)
- Yan Zhang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Yun Gao
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Fengyuan Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qi Qi
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qian Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yuanliang Gu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhonghua Zheng
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Beiping Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Tianpei Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Public Health Institute of Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Erbao Zhang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Liu
- Institute of Digestive Endoscopy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tian Tian
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, China
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China
- Public Health Institute of Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Caiwang Yan
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
- Department of Immunology, Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, China
- The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Wuxi, China
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10
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Yamaguchi N, Sakaguchi T, Taira M, Fukuda D, Ohnita K, Hirayama T, Yashima K, Isomoto H, Tsukamoto K. Autophagy-Related Gene ATG7 Polymorphism Could Potentially Serve as a Biomarker of the Progression of Atrophic Gastritis. J Clin Med 2024; 13:629. [PMID: 38276136 PMCID: PMC10817077 DOI: 10.3390/jcm13020629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 01/09/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
Cytotoxin-associated gene A (CagA) is an oncoprotein that H. pylori injects into the host's gastric epithelial cells and that induces proinflammatory cytokines, such as interleukin (IL)-18 and IL-1β. As a result, it leads to atrophic gastritis (AG), a precancerous lesion of gastric cancer. On the other hand, host cells degrade CagA using autophagy systems. However, few studies exist about the single nucleotide polymorphisms (SNPs) in MAP1LC3A, MAP1LC3B, ATG4A, ATG4B, ATG4C, ATG7, and ATG13, which belong to the autophagy-related genes concerning AG. This study aimed to detect biomarkers associated with AG. Herein, H. pylori-positive subjects (n = 200) were divided into the AG (n = 94) and non-AG (n = 106) groups. Thirty tag SNPs were selected from the above seven candidate genes. The SNP frequency between the two groups was analyzed. The frequency of the C/T or T/T genotype at rs4683787 of ATG7 was significantly lower in the AG group than in the non-AG group (p = 0.034, odds ratio = 0.535). Based on multivariate analysis, the C/C genotype of rs4684787 and age were independently associated with gastric mucosal atrophy. This finding helps stratify the patients needing timely endoscopic screening or early eradication of H. pylori.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Miki Taira
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Science, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki 850-0045, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kazuo Yashima
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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Pyun H, Gunathilake M, Lee J, Choi IJ, Kim YI, Sung J, Kim J. Functional Annotation and Gene Set Analysis of Gastric Cancer Risk Loci in a Korean Population. Cancer Res Treat 2024; 56:191-198. [PMID: 37340842 PMCID: PMC10789951 DOI: 10.4143/crt.2022.958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 06/17/2023] [Indexed: 06/22/2023] Open
Abstract
PURPOSE We aimed to identify the associated single nucleotide polymorphisms (SNPs) with gastric cancer (GC) risk by genome-wide association study (GWAS) and to explore the pathway enrichment of implicated genes and gene-sets with expression patterns. MATERIALS AND METHODS The study population was comprised of 1,253 GC cases and 4,827 controls from National Cancer Center and an urban community of the Korean Genome Epidemiology Study and their genotyping was performed. SNPs were annotated, and mapped to genes to prioritize by three mapping approaches by functional mapping and annotation (FUMA). The gene-based analysis and gene-set analysis were conducted with full GWAS summary data using MAGMA. Gene-set pathway enrichment test with those prioritized genes were performed. RESULTS In GWAS, rs2303771, a nonsynonymous variant of KLHDC4 gene was top SNP associated significantly with GC (odds ratio, 2.59; p=1.32×10-83). In post-GWAS, 71 genes were prioritized. In gene-based GWAS, seven genes were under significant p < 3.80×10-6 (0.05/13,114); DEFB108B had the lowest p=5.94×10-15, followed by FAM86C1 (p=1.74×10-14), PSCA (p=1.81×10-14), and KLHDC4 (p=5.00×10-10). In gene prioritizing, KLDHC4 was the only gene mapped with all three gene-mapping approaches. In pathway enrichment test with prioritized genes, FOLR2, PSCA, LY6K, LYPD2, and LY6E showed strong enrichment related to cellular component of membrane; a post-translation modification by synthesis of glycosylphosphatidylinositol (GPI)-anchored proteins pathway. CONCLUSION While 37 SNPs were significantly associated with the risk of GC, genes involved in signaling pathways related to purine metabolism and GPI-anchored protein in cell membrane are pinpointed to be playing important role in GC.
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Affiliation(s)
- Hyojin Pyun
- Division of Genome and Health Big Data, Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul,
Korea
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
| | - Madhawa Gunathilake
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
| | - Jeonghee Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
| | - Il Ju Choi
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang,
Korea
| | - Young-Il Kim
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang,
Korea
| | - Joohon Sung
- Division of Genome and Health Big Data, Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul,
Korea
- Institute of Health and Environment, Seoul National University, Seoul,
Korea
| | - Jeongseon Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
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12
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Hua H, Su T, Han L, Zhang L, Huang Y, Zhang N, Yang M. LINC01226 promotes gastric cancer progression through enhancing cytoplasm-to-nucleus translocation of STIP1 and stabilizing β-catenin protein. Cancer Lett 2023; 577:216436. [PMID: 37806517 DOI: 10.1016/j.canlet.2023.216436] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/10/2023]
Abstract
Gastric cancer (GC) remains one of the most common malignances and the leading cause of cancer-related mortality worldwide. Although the critical role of several long non-coding RNAs (lncRNAs) transcribed from several GC-risk loci has been established, we still know little about the biological significance of these lncRNAs at most gene loci and how they play in cell signaling. In the present study, we identified a novel oncogenic lncRNA LINC01226 transcribed from the 1p35.2 GC-risk locus. LINC01226 shows markedly higher expression levels in GC specimens compared with those in normal tissues. High expression of LINC01226 is evidently correlated with worse prognosis of GC cases. In line with these, oncogenic LINC01226 promotes proliferation, migration and metastasis of GC cells ex vivo and in vivo. Importantly, LINC01226 binds to STIP1 protein, leads to disassembly of the STIP1-HSP90 complex, elevates interactions between HSP90 and β-catenin, stabilizes β-catenin protein, activates the Wnt/β-catenin signaling and, thereby, promote GC progression. Together, our findings uncovered a novel layer regulating the Wnt signaling in cancers and uncovers a new epigenetic mode of GC tumorigenesis. These discoveries also shed new light on the importance of functional lncRNAs as innovative therapeutic targets through precisely controlling protein-protein interactions in cancers.
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Affiliation(s)
- Hui Hua
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Tao Su
- Shandong University Cancer Center, Jinan, Shandong Province, 250117, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Long Zhang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China; Shandong University Cancer Center, Jinan, Shandong Province, 250117, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
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13
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Ma HY, Das J, Prendergast C, De Jong D, Braumuller B, Paily J, Huang S, Liou C, Giarratana A, Hosseini M, Yeh R, Capaccione KM. Advances in CAR T Cell Therapy for Non-Small Cell Lung Cancer. Curr Issues Mol Biol 2023; 45:9019-9038. [PMID: 37998743 PMCID: PMC10670348 DOI: 10.3390/cimb45110566] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/25/2023] Open
Abstract
Since its first approval by the FDA in 2017, tremendous progress has been made in chimeric antigen receptor (CAR) T cell therapy, the adoptive transfer of engineered, CAR-expressing T lymphocyte. CAR T cells are all composed of three main elements: an extracellular antigen-binding domain, an intracellular signaling domain responsible for T cell activation, and a hinge that joins these two domains. Continuous improvement has been made in CARs, now in their fifth generation, particularly in the intracellular signaling domain responsible for T cell activation. CAR T cell therapy has revolutionized the treatment of hematologic malignancies. Nonetheless, the use of CAR T cell therapy for solid tumors has not attained comparable levels of success. Here we review the challenges in achieving effective CAR T cell therapy in solid tumors, and emerging CAR T cells that have shown great promise for non-small cell lung cancer (NSCLC). A growing number of clinical trials have been conducted to study the effect of CAR T cell therapy on NSCLC, targeting different types of surface antigens. They include epidermal growth factor receptor (EGFR), mesothelin (MSLN), prostate stem cell antigen (PSCA), and mucin 1 (MUC1). Potential new targets such as erythropoietin-producing hepatocellular carcinoma A2 (EphA2), tissue factor (TF), and protein tyrosine kinase 7 (PTK7) are currently under investigation in clinical trials. The challenges in developing CAR T for NSCLC therapy and other approaches for enhancing CAR T efficacy are discussed. Finally, we provide our perspective on imaging CAR T cell action by reviewing the two main radionuclide-based CAR T cell imaging techniques, the direct labeling of CAR T cells or indirect labeling via a reporter gene.
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Affiliation(s)
- Hong Yun Ma
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | - Jeeban Das
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Conor Prendergast
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | | | - Brian Braumuller
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | - Jacienta Paily
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | - Sophia Huang
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | - Connie Liou
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | - Anna Giarratana
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | - Mahdie Hosseini
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
| | - Randy Yeh
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Kathleen M. Capaccione
- Department of Radiology, Columbia University Irving Medica Center, 622 W 168th St., New York, NY 10032, USA; (H.Y.M.); (J.P.); (M.H.)
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14
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Iwasaki RL, Satta Y. Spatial and temporal diversity of positive selection on shared haplotypes at the PSCA locus among worldwide human populations. Heredity (Edinb) 2023; 131:156-169. [PMID: 37353592 PMCID: PMC10382566 DOI: 10.1038/s41437-023-00631-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 06/25/2023] Open
Abstract
Selection on standing genetic variation is important for rapid local genetic adaptation when the environment changes. We report that, for the prostate stem cell antigen (PSCA) gene, different populations have different target haplotypes, even though haplotypes are shared among populations. The C-C-A haplotype, whereby the first C is located at rs2294008 of PSCA and is a low risk allele for gastric cancer, has become a target of positive selection in Asia. Conversely, the C-A-G haplotype carrying the same C allele has become a selection target mainly in Africa. However, Asian and African share both haplotypes, consistent with the haplotype divergence time (170 kya) prior to the out-of-Africa dispersal. The frequency of C-C-A/C-A-G is 0.344/0.278 in Asia and 0.209/0.416 in Africa. Two-dimensional site frequency spectrum analysis revealed that the extent of intra-allelic variability of the target haplotype is extremely small in each local population, suggesting that C-C-A or C-A-G is under ongoing hard sweeps in local populations. From the time to the most recent common ancestor (TMRCA) of selected haplotypes, the onset times of positive selection were recent (3-55 kya), concurrently with population subdivision from a common ancestor. Additionally, estimated selection coefficients from ABC analysis were up to ~3%, similar to those at other loci under recent positive selection. Phylogeny of local populations and TMRCA of selected haplotypes revealed that spatial and temporal switching of positive selection targets is a unique and novel feature of ongoing selection at PSCA. This switching may reflect the potential of rapid adaptability to distinct environments.
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Affiliation(s)
- Risa L Iwasaki
- Department of Evolutionary Studies of Biosystems, School of Advanced Science, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa, 240-0193, Japan
- Research Center for Integrative Evolutionary Science, SOKENDAI, Hayama, Kanagawa, 240-0193, Japan
| | - Yoko Satta
- Department of Evolutionary Studies of Biosystems, School of Advanced Science, SOKENDAI (The Graduate University for Advanced Studies), Hayama, Kanagawa, 240-0193, Japan.
- Research Center for Integrative Evolutionary Science, SOKENDAI, Hayama, Kanagawa, 240-0193, Japan.
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15
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Mieno MN, Yamasaki M, Kuchiba A, Yamaji T, Ide K, Tanaka N, Sawada N, Inoue M, Tsugane S, Sawabe M, Iwasaki M. Lack of significant associations between single nucleotide polymorphisms in LPAL2-LPA genetic region and all cancer incidence and mortality in Japanese population: The Japan public health center-based prospective study. Cancer Epidemiol 2023; 85:102395. [PMID: 37321067 DOI: 10.1016/j.canep.2023.102395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/02/2023] [Accepted: 05/25/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND High lipoprotein (a) level is an established cardiovascular risk, but its association with non-cardiovascular diseases, especially cancer, is controversial. Serum lipoprotein (a) levels vary widely by genetic backgrounds and are largely determined by the genetic variations of apolipoprotein (a) gene, LPA. In this study, we investigate the association between SNPs in LPA region and cancer incidence and mortality in Japanese. METHODS A genetic cohort study was conducted utilizing the data from 9923 participants in the Japan Public Health Center-based Prospective Study (JPHC Study). Twenty-five SNPs in the LPAL2-LPA region were selected from the genome-wide genotyped data. Cox regression analysis adjusted for the covariates and competing risks of death from other causes, were used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of overall and site-specific cancer incidence and mortality, for each SNP. RESULTS No significant association was found between SNPs in the LPAL2-LPA region and cancer incidence or mortality (overall/site-specific cancer). In men, however, HRs for stomach cancer incidence of 18SNPs were estimated higher than 1.5 (e.g., 2.15 for rs13202636, model free, 95%CI: 1.28-3.62) and those for stomach cancer mortality of 2SNPs (rs9365171, rs1367211) were estimated 2.13 (recessive, 95%CI:1.04-4.37) and 1.61 (additive, 95%CI: 1.00-2.59). Additionally, the minor allele for SNP rs3798220 showed increased death risk from colorectal cancer (CRC) in men (HR: 3.29, 95% CI:1.59 - 6.81) and decreased CRC incidence risk in women (HR: 0.46, 95%CI: 0.22-0.94). Minor allele carrier of any of 4SNPs could have risk of prostate cancer incidence (e.g., rs9365171 dominant, HR: 1.71, 95%CI: 1.06-2.77). CONCLUSIONS None of the 25 SNPs in the LPAL2-LPA region was found to be significantly associated with cancer incidence or mortality. Considering the possible association between SNPs in LPAL2-LPA region and colorectal, prostate and stomach cancer incidence or mortality, further analysis using different cohorts is warranted.
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Affiliation(s)
- Makiko Naka Mieno
- Department of Medical Informatics, Center for Information, Jichi Medical University, Shimotsuke 329-0498, Japan; Health Data Science Research Section, Healthy Aging Innovation Center, Tokyo Metropolitan Geriatric Research Institute, Tokyo 173-0015, Japan
| | - Maria Yamasaki
- Health Data Science Research Section, Healthy Aging Innovation Center, Tokyo Metropolitan Geriatric Research Institute, Tokyo 173-0015, Japan
| | - Aya Kuchiba
- Biostatistics Division, Center for Research Administration and Support/Division of Biostatistical Research, Institute for Cancer Control, National Cancer Center, Tokyo 104-0045, Japan; Graduate School of Health Innovation, Kanagawa University of Human Services, Kanagawa, 210-0821, Japan
| | - Taiki Yamaji
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan.
| | - Keigo Ide
- Health Data Science Research Section, Healthy Aging Innovation Center, Tokyo Metropolitan Geriatric Research Institute, Tokyo 173-0015, Japan; Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan
| | - Noriko Tanaka
- Health Data Science Research Section, Healthy Aging Innovation Center, Tokyo Metropolitan Geriatric Research Institute, Tokyo 173-0015, Japan.
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan
| | - Manami Inoue
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan; Division of Prevention, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan
| | - Shoichiro Tsugane
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan; National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo 162-8636, Japan
| | - Motoji Sawabe
- Department of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan; Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan
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16
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Hess T, Maj C, Gehlen J, Borisov O, Haas SL, Gockel I, Vieth M, Piessen G, Alakus H, Vashist Y, Pereira C, Knapp M, Schüller V, Quaas A, Grabsch HI, Trautmann J, Malecka-Wojciesko E, Mokrowiecka A, Speller J, Mayr A, Schröder J, Hillmer AM, Heider D, Lordick F, Pérez-Aísa Á, Campo R, Espinel J, Geijo F, Thomson C, Bujanda L, Sopeña F, Lanas Á, Pellisé M, Pauligk C, Goetze TO, Zelck C, Reingruber J, Hassanin E, Elbe P, Alsabeah S, Lindblad M, Nilsson M, Kreuser N, Thieme R, Tavano F, Pastorino R, Arzani D, Persiani R, Jung JO, Nienhüser H, Ott K, Schumann RR, Kumpf O, Burock S, Arndt V, Jakubowska A, Ławniczak M, Moreno V, Martín V, Kogevinas M, Pollán M, Dąbrowska J, Salas A, Cussenot O, Boland-Auge A, Daian D, Deleuze JF, Salvi E, Teder-Laving M, Tomasello G, Ratti M, Senti C, De Re V, Steffan A, Hölscher AH, Messerle K, Bruns CJ, Sīviņš A, Bogdanova I, Skieceviciene J, Arstikyte J, Moehler M, Lang H, Grimminger PP, Kruschewski M, Vassos N, Schildberg C, Lingohr P, Ridwelski K, Lippert H, Fricker N, Krawitz P, Hoffmann P, Nöthen MM, Veits L, Izbicki JR, Mostowska A, Martinón-Torres F, Cusi D, Adolfsson R, Cancel-Tassin G, Höblinger A, Rodermann E, Ludwig M, Keller G, Metspalu A, Brenner H, Heller J, Neef M, Schepke M, Dumoulin FL, Hamann L, Cannizzaro R, Ghidini M, Plaßmann D, Geppert M, Malfertheiner P, Gehlen O, Skoczylas T, Majewski M, Lubiński J, Palmieri O, Boccia S, Latiano A, Aragones N, Schmidt T, Dinis-Ribeiro M, Medeiros R, Al-Batran SE, Leja M, Kupcinskas J, García-González MA, Venerito M, Schumacher J. Dissecting the genetic heterogeneity of gastric cancer. EBioMedicine 2023; 92:104616. [PMID: 37209533 DOI: 10.1016/j.ebiom.2023.104616] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/28/2023] [Accepted: 04/30/2023] [Indexed: 05/22/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. METHODS We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. FINDINGS Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. INTERPRETATION Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. FUNDING German Research Foundation (DFG).
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Affiliation(s)
- Timo Hess
- Institute of Human Genetics, University of Marburg, Marburg, Germany; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Carlo Maj
- Institute of Human Genetics, University of Marburg, Marburg, Germany; Medical Faculty, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
| | - Jan Gehlen
- Institute of Human Genetics, University of Marburg, Marburg, Germany
| | - Oleg Borisov
- Medical Faculty, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
| | - Stephan L Haas
- Department of Upper GI Diseases, Karolinska Institutet, Karolinska University Hospital and Unit of Gastroenterology and Rheumatology, Stockholm, Sweden
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Michael Vieth
- Institute for Pathology, Friedrich-Alexander-University Erlangen-Nuernberg, Klinikum Bayreuth, Bayreuth, Germany
| | - Guillaume Piessen
- Department of Digestive and Oncological Surgery, Claude Huriez Hospital, CHU Lille, Lille, France
| | - Hakan Alakus
- Department of General, Visceral, Cancer and Transplant Surgery, University of Cologne, Cologne, Germany
| | - Yogesh Vashist
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany; Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
| | - Carina Pereira
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO Porto), Porto 4200-072, Portugal; Porto Comprehensive Cancer Center & RISE @ CI-IPO, University of Porto, Porto 4200-450, Portugal
| | - Michael Knapp
- Medical Faculty, Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany
| | - Vitalia Schüller
- Institute of Human Genetics, University of Marburg, Marburg, Germany
| | - Alexander Quaas
- Medical Faculty, Institute of Pathology, University Hospital Cologne, University of Cologne, Germany
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Jessica Trautmann
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | | | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Jan Speller
- Medical Faculty, Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany
| | - Andreas Mayr
- Medical Faculty, Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany
| | - Julia Schröder
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Axel M Hillmer
- Medical Faculty, Institute of Pathology, University Hospital Cologne, University of Cologne, Germany
| | - Dominik Heider
- Department of Mathematics and Computer Science, University of Marburg, Marburg, Germany
| | - Florian Lordick
- University Cancer Center Leipzig, Leipzig University Medical Center, Leipzig, Germany
| | | | - Rafael Campo
- Department of Gastroenterology, Hospital Parc Tauli, Sabadell, Spain
| | - Jesús Espinel
- Department of Gastroenterology, Complejo Hospitalario, León, Spain
| | - Fernando Geijo
- Department of Gastroenterology, Hospital Clínico Universitario, Salamanca, Spain
| | - Concha Thomson
- Department of Gastroenterology, Hospital Obispo Polanco, Teruel, Spain
| | - Luis Bujanda
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Federico Sopeña
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Ángel Lanas
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain
| | - María Pellisé
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Department of Gastroenterology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Claudia Pauligk
- Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany; Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Thorsten Oliver Goetze
- Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany; Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Carolin Zelck
- Institute of Human Genetics, University of Marburg, Marburg, Germany
| | - Julian Reingruber
- Institute of Human Genetics, University of Marburg, Marburg, Germany
| | - Emadeldin Hassanin
- Medical Faculty, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
| | - Peter Elbe
- Department of Upper GI Diseases, Karolinska Institutet, Karolinska University Hospital and Unit of Gastroenterology and Rheumatology, Stockholm, Sweden
| | - Sandra Alsabeah
- Department of Upper GI Diseases, Karolinska Institutet, Karolinska University Hospital and Unit of Gastroenterology and Rheumatology, Stockholm, Sweden
| | - Mats Lindblad
- Division of Surgery, Department of Upper GI Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Nilsson
- Division of Surgery, Department of Upper GI Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Francesca Tavano
- Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Roberta Pastorino
- Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Dario Arzani
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Roberto Persiani
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Jin-On Jung
- Department of General, Visceral, Cancer and Transplant Surgery, University of Cologne, Cologne, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Henrik Nienhüser
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Katja Ott
- Department of Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Ralf R Schumann
- Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Oliver Kumpf
- Department of Anaesthesiology and Operative Intensive Care Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Susen Burock
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anna Jakubowska
- Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, Poland
| | - Małgorzta Ławniczak
- Department of Gastroenterology, Pomeranian Medical University in Szczecin, Poland
| | - Victor Moreno
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), Hospital Duran I Reynals, Barcelona, Spain; Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Faculty of Medicine, Department of Clinical Sciences, University of Barcelona, Barcelona, Spain
| | - Vicente Martín
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública e CIBERESP), Spain; The Research Group in Gene - Environment and Health Interactions (GIIGAS)/Institute of Biomedicine (IBIOMED), Universidad de Leon, Leon, Spain; Faculty of Health Sciences, Department of Biomedical Sciences, Area of Preventive Medicine and Public Health, Universidad de Leon, Leon, Spain
| | - Manolis Kogevinas
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública e CIBERESP), Spain; ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Campus Del Mar, Barcelona, Spain; IMIM (Hospital Del Mar Medical Research Institute), Barcelona, Spain
| | - Marina Pollán
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública e CIBERESP), Spain; Cancer and Environmental Epidemiology Unit, Department of Epidemiology of Chronic Diseases, National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain
| | - Justyna Dąbrowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poland
| | - Antonio Salas
- Unidade de Xenética, Instituto de Ciencias Forenses (INCIFOR), Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain; GenPoB Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario de Santiago (SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBER-ES), Madrid, Spain
| | - Olivier Cussenot
- CeRePP, Paris, France; GRC n°5 Predictive Onco-Urology, Tenon Hospital, Sorbonne University, Paris, France
| | - Anne Boland-Auge
- Centre National de Recherche en Génomique Humaine, CEA, University Paris-Saclay, Evry, France
| | - Delphine Daian
- Centre National de Recherche en Génomique Humaine, CEA, University Paris-Saclay, Evry, France
| | - Jean-Francois Deleuze
- Centre National de Recherche en Génomique Humaine, CEA, University Paris-Saclay, Evry, France
| | - Erika Salvi
- Neuroalgology Unit Fondazione IRCCS, Instituto Neurologico 'Carlo Besta' Milan, Milan, Italy
| | - Maris Teder-Laving
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Gianluca Tomasello
- Medical Oncology Unit, ASST of Cremona, Cremona, Italy; Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Chiara Senti
- Medical Oncology Unit, ASST of Cremona, Cremona, Italy; Department of Medical Oncology, Institut Jules Bordet - Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Valli De Re
- Unit of Immunopathologia e Biomarcatori Oncologici/Bio-proteomics Facility, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Agostino Steffan
- Unit of Immunopathologia e Biomarcatori Oncologici, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Arnulf H Hölscher
- Department of General, Visceral, Cancer and Transplant Surgery, University of Cologne, Cologne, Germany
| | - Katharina Messerle
- Department of General, Visceral, Cancer and Transplant Surgery, University of Cologne, Cologne, Germany
| | | | - Armands Sīviņš
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga East University Hospital, Riga, Latvia
| | - Inga Bogdanova
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga East University Hospital, Riga, Latvia
| | - Jurgita Skieceviciene
- Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Justina Arstikyte
- Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Markus Moehler
- Department of Medicine I, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Peter P Grimminger
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Martin Kruschewski
- Department of General and Visceral Surgery, Klinikum Frankfurt (Oder), Germany
| | - Nikolaos Vassos
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Claus Schildberg
- Department of General Surgery, Brandenburg Medical School Theodor Fontane, University Hospital Brandenburg, Brandenburg, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Karsten Ridwelski
- Department of General and Visceral Surgery, Klinikum Magdeburg GmbH, Magdeburg, Germany
| | - Hans Lippert
- Institute of Quality Assurance in Operative Medicine, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Nadine Fricker
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Peter Krawitz
- Medical Faculty, Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
| | - Per Hoffmann
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | - Lothar Veits
- Institute for Pathology, Friedrich-Alexander-University Erlangen-Nuernberg, Klinikum Bayreuth, Bayreuth, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
| | - Adrianna Mostowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poland
| | - Federico Martinón-Torres
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBER-ES), Madrid, Spain; Department of Pediatrics, Translational Pediatrics and Infectious Diseases Section, Hospital Clínico Universitario de Santiago (SERGAS), Santiago de Compostela, Spain; Genetics, Vaccines, Infectious Diseases and Pediatrics Research Group GENVIP, Instituto de Investigación Sanitaria de Santiago (IDIS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Daniele Cusi
- Institute of Biomedical Technologies, National Research Council of Italy, Milan, Italy; Bio4Dreams-Business, Nursery for Life Sciences, Milan, Italy
| | - Rolf Adolfsson
- Department of Clinical Sciences, Umeå University, Umeå, Sweden
| | - Geraldine Cancel-Tassin
- CeRePP, Paris, France; GRC n°5 Predictive Onco-Urology, Tenon Hospital, Sorbonne University, Paris, France
| | - Aksana Höblinger
- Department of Internal Medicine I, Community Hospital Mittelrhein, Koblenz, Germany
| | - Ernst Rodermann
- Association of Medical Practices in Hematology and Internal Oncology, Troisdorf, Germany
| | - Monika Ludwig
- Association for Oncological Studies (Gefos), Dortmund, Germany
| | - Gisela Keller
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Andres Metspalu
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Joerg Heller
- Department of Gastroenterology, Marienhaus Hospital Ahrweiler, Ahrweiler, Germany
| | - Markus Neef
- Department of Gastroenterology, Helios Hospital Siegburg, Siegburg, Germany
| | - Michael Schepke
- Department of Gastroenterology, Helios Hospital Siegburg, Siegburg, Germany
| | | | - Lutz Hamann
- Institute of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Renato Cannizzaro
- Unit of Oncological Gastroenterology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
| | - Michele Ghidini
- Medical Oncology Unit, ASST of Cremona, Cremona, Italy; Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | | | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany; Department of Internal Medicine II, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany
| | - Olivier Gehlen
- Department of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France
| | - Tomasz Skoczylas
- 2nd Department of General Surgery, Medical University of Lublin, Lublin, Poland
| | - Marek Majewski
- 2nd Department of General Surgery, Medical University of Lublin, Lublin, Poland
| | - Jan Lubiński
- Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Poland
| | - Orazio Palmieri
- Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Stefania Boccia
- Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Anna Latiano
- Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Nuria Aragones
- Consortium for Biomedical Research in Epidemiology & Public Health (CIBER en Epidemiología y Salud Pública e CIBERESP), Spain; Epidemiology Section, Public Health Division, Department of Health of Madrid, Madrid, Spain
| | - Thomas Schmidt
- Department of General, Visceral, Cancer and Transplant Surgery, University of Cologne, Cologne, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Mário Dinis-Ribeiro
- Porto Comprehensive Cancer Center & RISE @ CI-IPO, University of Porto, Porto 4200-450, Portugal; Gastroenterology Department, Portuguese Institute of Oncology of Porto, Porto 4200-072, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO Porto), Porto 4200-072, Portugal; Research Department of the Portuguese League Against Cancer-North (LPCC-NRNorte), Porto 4200-177, Portugal
| | - Salah-Eddin Al-Batran
- Krankenhaus Nordwest, University Cancer Center, Frankfurt, Germany; Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Mārcis Leja
- Institute of Clinical and Preventive Medicine, University of Latvia, Riga East University Hospital, Riga, Latvia; Digestive Diseases Centre GASTRO, Riga, Latvia
| | - Juozas Kupcinskas
- Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - María A García-González
- CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
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Yamaguchi N, Sakaguchi T, Isomoto H, Inamine T, Tsukamoto R, Fukuda D, Ohnita K, Kanda T, Matsushima K, Hirayama T, Yashima K, Tsukamoto K. Polymorphism in autophagy-related genes LRP1 and CAPZA1 may promote gastric mucosal atrophy. Genes Environ 2023; 45:18. [PMID: 37198664 DOI: 10.1186/s41021-023-00274-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 04/27/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Helicobacter pylori secretes cytotoxin-associated gene A (CagA) into the gastric epithelium, causing gastric mucosal atrophy (GMA) and gastric cancer. In contrast, host cells degrade CagA via autophagy. However, the association between polymorphisms in autophagy-related genes and GMA must be fully elucidated. RESULTS We evaluated the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (low-density lipoprotein receptor-related protein 1, LRP1; capping actin protein of muscle Z-line alpha subunit 1, CAPAZ1; and lysosomal-associated membrane protein 1, LAMP1) and GMA in 200 H. pylori-positive individuals. The frequency of the T/T genotype at rs1800137 in LRP1 was significantly lower in the GMA group than in the non-GMA group (p = 0.018, odds ratio [OR] = 0.188). The frequencies of the G/A or A/A genotype at rs4423118 and T/A or A/A genotype at rs58618380 of CAPAZ1 in the GMA group were significantly higher than those in the non-GMA group (p = 0.029 and p = 0.027, respectively). Multivariate analysis revealed that C/C or C/T genotype at rs1800137, T/A or A/A genotype at rs58618380, and age were independent risk factors for GMA (p = 0.038, p = 0.023, and p = 0.006, respectively). Furthermore, individuals with the rs1800137 C/C or C/T genotype of LRP1 had a 5.3-fold higher susceptibility to GMA. These genetic tests may provide future directions for precision medicine for individuals more likely to develop GMA. CONCLUSION LRP1 and CAPZA1 polymorphisms may be associated with the development of GMA.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan.
| | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan.
| | - Tatsuo Inamine
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Ryoya Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki, 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki, 850-0045, Japan
| | - Tsutomu Kanda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan
| | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Kazuo Yashima
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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18
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Rathbun LA, Magliocco AM, Bamezai AK. Human LY6 gene family: potential tumor-associated antigens and biomarkers of prognosis in uterine corpus endometrial carcinoma. Oncotarget 2023; 14:426-437. [PMID: 37141412 PMCID: PMC10159366 DOI: 10.18632/oncotarget.28409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023] Open
Abstract
The human Lymphocyte antigen-6 (LY6) gene family has recently gained interest for its possible role in tumor progression. We have carried out in silico analyses of all known LY6 gene expression and amplification in different cancers using TNMplot and cBioportal. We also have analyzed patient survival by Kaplan-Meier plotter after mining the TCGA database. We report that upregulated expression of many LY6 genes is associated with poor survival in uterine corpus endometrial carcinoma (UCEC) cancer patients. Importantly, the expression of several LY6 genes is elevated in UCEC when compared to the expression in normal uterine tissue. For example, LY6K expression is 8.25× higher in UCEC compared to normal uterine tissue, and this high expression is associated with poor survival with a hazard ratio of 2.42 (p-value = 0.0032). Therefore, some LY6 gene products may serve as tumor-associated antigens in UCEC, biomarkers for UCEC detection, and possibly targets for directing UCEC patient therapy. Further analysis of tumor-specific expression of LY6 gene family members and LY6-triggered signaling pathways is needed to uncover the function of LY6 proteins and their ability to endow tumor survival and poor prognosis in UCEC patients.
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Affiliation(s)
- Luke A Rathbun
- Department of Biology, Villanova University, Villanova, PA 19085, USA
| | | | - Anil K Bamezai
- Department of Biology, Villanova University, Villanova, PA 19085, USA
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19
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Zhang N, Wang B, Ma C, Zeng J, Wang T, Han L, Yang M. LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization. J Exp Clin Cancer Res 2023; 42:89. [PMID: 37072811 PMCID: PMC10111703 DOI: 10.1186/s13046-023-02654-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 03/25/2023] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND Gastric cancer remains the leading cause of cancer death in the world. It is increasingly evident that long non-coding RNAs (lncRNAs) transcribed from the genome-wide association studies (GWAS)-identified gastric cancer risk loci act as a key mode of cancer development and disease progression. However, the biological significance of lncRNAs at most cancer risk loci remain poorly understood. METHODS The biological functions of LINC00240 in gastric cancer were investigated through a series of biochemical assays. Clinical implications of LINC00240 were examined in tissues from gastric cancer patients. RESULTS In the present study, we identified LINC00240, which is transcribed from the 6p22.1 gastric cancer risk locus, functioning as a novel oncogene. LINC00240 exhibits the noticeably higher expression in gastric cancer specimens compared with normal tissues and its high expression levels are associated with worse survival of patients. Consistently, LINC00240 promotes malignant proliferation, migration and metastasis of gastric cancer cells in vitro and in vivo. Importantly, LINC00240 could interact and stabilize oncoprotein DDX21 via eliminating its ubiquitination by its novel deubiquitinating enzyme USP10, which, thereby, promote gastric cancer progression. CONCLUSIONS Taken together, our data uncovered a new paradigm on how lncRNAs control protein deubiquitylation via intensifying interactions between the target protein and its deubiquitinase. These findings highlight the potentials of lncRNAs as innovative therapeutic targets and thus lay the ground work for clinical translation.
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Affiliation(s)
- Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China
| | - Bowen Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China
| | - Chi Ma
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China
- Department of Thyroid Surgery, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Shandong Province, Yantai, 264000, China
| | - Jiajia Zeng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China
| | - Teng Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Province, Jinan, 250117, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
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Wang XF, Liu DL, Geng L. The PSCA rs2294008 (C/T) Polymorphism Increases the Risk of Gastric and Bladder Cancer: A Meta-Analysis. Genet Test Mol Biomarkers 2023; 27:44-55. [PMID: 36853840 DOI: 10.1089/gtmb.2022.0067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023] Open
Abstract
Background: It has been reported that prostate stem cell antigen (PSCA) is overexpressed in certain cancer types and confers poor prognoses. The rs2294008 (C/T) polymorphism of PSCA is considered to be associated with risk for gastric, bladder, and colorectal cancers; however, these studies have produced inconsistent results, so we performed this meta-analysis to verify the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. Methods: A systematic literature search was performed using PubMed, EMBASE, and the Chinese National Knowledge Infrastructure, through October 20, 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. In addition, we explored PSCA mRNA expression in cancers through online databases. Results: In total, 45 articles met our inclusion criteria and were analyzed, including 37,586 cancer cases and 51,197 non-cancer controls. Except in the recessive model, the pooled effect indicated the PSCA rs2294008 T allele was associated with an increased overall cancer risk (T vs. C: OR = 1.120, 95% CI = 1.056-1.188, p < 0.01; TT vs. CC: OR = 1.206, 95% CI = 1.066-1.364, p = 0.03; CT vs. CC: OR = 1.249, 95% CI = 1.151-1.356, p < 0.01; [CT+TT] vs. CC: OR = 1.248, 95% CI = 1.147-1.359, p < 0.01; TT vs. [CT+CC]: OR = 1.051, 95% CI = 0.954-1.156, p = 0.314). In the subgroup analysis, there were significant associations between the rs2294008 T allele and increased risk of bladder and gastric cancer. Two different online tools were used to explore the PSCA mRNA levels in cancer and the corresponding normal adjacent tissues. We found that expression of PSCA was significantly lower in gastric cancer patients. Conclusions: The PSCA rs2294008 T polymorphism is related to increased cancer susceptibility, especially for gastric and bladder cancers. This polymorphism results in a decreased PSCA expression level in gastric cancer.
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Affiliation(s)
- Xiao-Feng Wang
- Department of Medical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dong-Li Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Ministry of Education, Shanghai, China
| | - Li Geng
- Department of Medical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Helicobacter pylori shows tropism to gastric differentiated pit cells dependent on urea chemotaxis. Nat Commun 2022; 13:5878. [PMID: 36198679 PMCID: PMC9535007 DOI: 10.1038/s41467-022-33165-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/06/2022] [Indexed: 11/09/2022] Open
Abstract
The human gastric epithelium forms highly organized gland structures with different subtypes of cells. The carcinogenic bacterium Helicobacter pylori can attach to gastric cells and subsequently translocate its virulence factor CagA, but the possible host cell tropism of H. pylori is currently unknown. Here, we report that H. pylori preferentially attaches to differentiated cells in the pit region of gastric units. Single-cell RNA-seq shows that organoid-derived monolayers recapitulate the pit region, while organoids capture the gland region of the gastric units. Using these models, we show that H. pylori preferentially attaches to highly differentiated pit cells, marked by high levels of GKN1, GKN2 and PSCA. Directed differentiation of host cells enable enrichment of the target cell population and confirm H. pylori preferential attachment and CagA translocation into these cells. Attachment is independent of MUC5AC or PSCA expression, and instead relies on bacterial TlpB-dependent chemotaxis towards host cell-released urea, which scales with host cell size. The carcinogenic bacterium Helicobacter pylori infects gastric cells. Here, the authors show that H. pylori preferentially infects differentiated cells in the pit region of gastric units, and this relies on bacterial chemotaxis towards host cell-released urea, which scales with host cell size.
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22
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Choi HG, Chun W, Jung KH. Association between gastric cancer and the family history of gastric cancer: a cross-sectional study using Korean Genome and Epidemiology Study data. Eur J Cancer Prev 2022; 31:408-414. [PMID: 34860707 DOI: 10.1097/cej.0000000000000724] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The risk of gastric cancer based on a family history of gastric cancer remains unclear. The purpose of this study was to investigate the relationship between gastric cancer and family history of gastric cancer within a large cohort in Korea. METHODS In total 211 708 participants were recruited in the Korean Genome and Epidemiology Study during 2001-2013, and divided into a group with a self-reported personal history of gastric cancer ( n = 930) and a 1:40 matched control group ( n = 37 200). We examined the family history of gastric cancer in first-degree relatives for cross-sectional analysis. Logistic regression was used to estimate the odds ratios (ORs) of gastric cancer according to family history, using four models that were adjusted for different confounding variables, including the interaction among a family history of gastric cancer. RESULTS After matching the two groups for age and sex, the gastric cancer group had a significantly higher proportion of family history in each relative than the controls ( P < 0.001). In the adjusted model, the ORs [95% confidence interval (CI)] for gastric cancer with a history of an affected father, mother and sibling were 1.80 (1.38-2.34), 1.95 (1.42-2.69) and 2.98 (2.31-3.83), respectively, compared with those in the control group. There was no statistically significant interaction among a family history of gastric cancer in each relative. CONCLUSION A history of gastric cancer in siblings, among first-degree relatives, is strongly associated with an increased risk of gastric cancer. Regular follow-up and early treatment are recommended for those with a family history of gastric cancer.
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Affiliation(s)
- Hyo Geun Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine
- Hallym Data Science Laboratory, Hallym University College of Medicine, Anyang
| | - Wook Chun
- Department of Surgery, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul
| | - Kuk Hyun Jung
- Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
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23
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Lee S, Yang HK, Lee HJ, Park DJ, Kong SH, Park SK. Systematic review of gastric cancer-associated genetic variants, gene-based meta-analysis, and gene-level functional analysis to identify candidate genes for drug development. Front Genet 2022; 13:928783. [PMID: 36081994 PMCID: PMC9446437 DOI: 10.3389/fgene.2022.928783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 07/25/2022] [Indexed: 12/05/2022] Open
Abstract
Objective: Despite being a powerful tool to identify novel variants, genome-wide association studies (GWAS) are not sufficient to explain the biological function of variants. In this study, we aimed to elucidate at the gene level the biological mechanisms involved in gastric cancer (GC) development and to identify candidate drug target genes. Materials and methods: We conducted a systematic review for GWAS on GC following the PRISMA guidelines. Single nucleotide polymorphism (SNP)-level meta-analysis and gene-based analysis (GBA) were performed to identify SNPs and genes significantly associated with GC. Expression quantitative trait loci (eQTL), disease network, pathway enrichment, gene ontology, gene-drug, and chemical interaction analyses were conducted to elucidate the function of the genes identified by GBA. Results: A review of GWAS on GC identified 226 SNPs located in 91 genes. In the comprehensive GBA, 44 genes associated with GC were identified, among which 12 genes (THBS3, GBAP1, KRTCAP2, TRIM46, HCN3, MUC1, DAP3, EFNA1, MTX1, PRKAA1, PSCA, and ABO) were eQTL. Using disease network and pathway analyses, we identified that PRKAA, THBS3, and EFNA1 were significantly associated with the PI3K-Alt-mTOR-signaling pathway, which is involved in various oncogenic processes, and that MUC1 acts as a regulator in both the PI3K-Alt-mTOR and P53 signaling pathways. Furthermore, RPKAA1 had the highest number of interactions with drugs and chemicals. Conclusion: Our study suggests that PRKAA1, a gene in the PI3K-Alt-mTOR-signaling pathway, could be a potential target gene for drug development associated with GC in the future. Systematic Review Registration: website, identifier registration number.
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Affiliation(s)
- Sangjun Lee
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
| | - Han-Kwang Yang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyuk-Joon Lee
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Do Joong Park
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seong-Ho Kong
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Sue K. Park
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea
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Isomoto H, Sakaguchi T, Inamine T, Takeshita S, Fukuda D, Ohnita K, Kanda T, Matsushima K, Honda T, Sugihara T, Hirayama T, Nakao K, Tsukamoto K. SNP rs2920280 in PSCA Is Associated with Susceptibility to Gastric Mucosal Atrophy and Is a Promising Biomarker in Japanese Individuals with Helicobacter pylori Infection. Diagnostics (Basel) 2022; 12:diagnostics12081988. [PMID: 36010338 PMCID: PMC9407312 DOI: 10.3390/diagnostics12081988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 11/16/2022] Open
Abstract
Helicobacter pylori infection results in gastric cancer (GC) with gastric mucosal atrophy (GMA). Some single-nucleotide polymorphisms (SNPs) in the prostate stem cell antigen gene (PSCA) are associated with GC and duodenal ulcers. However, the relationship of other identified SNPs in PSCA with these diseases remains unclear. Herein, the association between PSCA SNPs and GMA among 195 Japanese individuals with H. pylori infection was evaluated. The definition of GMA or non-GMA was based on serum pepsinogen levels or endoscopic findings. Five tag PSCA SNPs were analyzed using PCR high-resolution melting curve analysis with nonlabelled probes. The frequencies of alleles and the genotypes of each tag SNP were compared between the GMA and non-GMA groups. Subsequently, a genetic test was performed using associated SNPs as biomarkers to detect patients developing GMA. Two tag PSCA SNPs (rs2920280 and rs2294008) were related to GMA susceptibility. Individuals with the rs2920280 G/G genotype or the rs2294008 T/T genotype in PSCA had 3.5- and 2.1-fold susceptibility to GMA, respectively. In conclusion, SNP rs2920280 is a possible biomarker for detecting individuals developing GMA. PSCA polymorphisms may be useful biomarkers for predicting GMA linked to GC risk and a screening endoscopy strategy to detect GC related to early stage H. pylori associated GMA.
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Affiliation(s)
- Hajime Isomoto
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Correspondence: (H.I.); (T.S.); Tel.: +81-859-38-6527 (H.I.)
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
- Correspondence: (H.I.); (T.S.); Tel.: +81-859-38-6527 (H.I.)
| | - Tatsuo Inamine
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Shintaro Takeshita
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Surgical Oncology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Fukuda Yutaka Clinic, 3-5 Hamaguchi-machi, Nagasaki 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki 850-0045, Japan
| | - Tsutomu Kanda
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Tetsuro Honda
- Department of Gastroenterology, Nagasaki Medical Harbor Center, 6-39 Shinchi-machi, Nagasaki 850-8555, Japan
| | - Takaaki Sugihara
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biological Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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Fan P, Zhang Z, Lu L, Guo X, Hao Z, Wang X, Ye Y. Association of single nucleotide polymorphisms (SNPs) with gastric cancer susceptibility and prognosis in population in Wuwei, Gansu, China. World J Surg Oncol 2022; 20:194. [PMID: 35689286 PMCID: PMC9188220 DOI: 10.1186/s12957-022-02663-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 05/21/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is the sixth most common cancer. China is one of the most frequent GC occurred countries, and Wuwei, Gansu, is one of the highest incidence area in China. Possible biomarkers of GC susceptibility and prognosis among the population in Wuwei are urgently needed. METHODS All participants in this study were recruited from the Wuwei Cancer Hospital in Gansu, including 303 patients diagnosed with GC and 200 non-cancer controls. DNA was extracted for further single nucleotide polymorphisms (SNP) genotyping. All SNPs were firstly screened by additive logistic regression model then selected SNPs were subjected to univariate Cox regression analysis and multivariate Cox regression analysis for their associations with GC occurrence. RESULTS The results showed that 31 SNPs were significantly related to the incidence of GC in Wuwei, Gansu, China. Genotype rs4823921 was significantly related to the overall survival of GC patients and AC/AA genotype of rs4823921 polymorphism was significantly associated with an increased risk of GC in Wuwei population. CONCLUSIONS Thirty-one SNPs were significantly related to the incidence of GC in Wuwei and rs4823921 genotype AC/AA was significantly associated with poor prognosis of GC patients in Wuwei, Gansu.
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Affiliation(s)
- Ping Fan
- Department of Pathology, Gansu Wuwei Tumor Hospital, Wuwei, 730000, Gansu, China
| | - Zhiyi Zhang
- Department of Gastroenterology, Gansu Wuwei Tumor Hospital, Wuwei, 730000, Gansu, China
| | - Linzhi Lu
- Department of Gastroenterology, Gansu Wuwei Tumor Hospital, Wuwei, 730000, Gansu, China
| | - Xingcai Guo
- Biochip Center, Gansu Wuwei Tumor Hospital, Wuwei, 730000, Gansu, China
| | - Zhicheng Hao
- Biochip Center, Gansu Wuwei Tumor Hospital, Wuwei, 730000, Gansu, China
| | - Xinghua Wang
- Biobank, Gansu Wuwei Tumor Hospital, Wuwei, 730000, Gansu, China
| | - Yancheng Ye
- Department of Pharmacy, Gansu Wuwei Tumor Hospital, Wuwei, 730000, Gansu, China.
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Lam SY, Mommersteeg MC, Yu B, Broer L, Spaander MCW, Frost F, Weiss S, Völzke H, Lerch MM, Schöttker B, Zhang Y, Stocker H, Brenner H, Levy D, Hwang SJ, Wood AC, Rich SS, Rotter JI, Taylor KD, Tracy RP, Kabagambe EK, Leja M, Klovins J, Peculis R, Rudzite D, Nikitina-Zake L, Skenders G, Rovite V, Uitterlinden A, Kuipers EJ, Fuhler GM, Homuth G, Peppelenbosch MP. Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti-Helicobacter pylori IgG Titers. Gastroenterology 2022; 162:1705-1715. [PMID: 35031300 PMCID: PMC11734630 DOI: 10.1053/j.gastro.2022.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 12/03/2021] [Accepted: 01/07/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS A genome-wide significant association between anti-Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. METHODS The dichotomous GWAS (25% individuals exhibiting highest anti-H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori-eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. RESULTS The association of the TLR1/6/10 locus with anti-H pylori IgG titers (rs12233670; β = -0.267 ± SE 0.034; P = 4.42 × 10-15) presented with high heterogeneity and failed replication. Anti-H pylori IgG titers declined within 2-4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. CONCLUSIONS The association between anti-H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti-H pylori IgG titers on therapy, clearance, and antibody decay. H pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.
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Affiliation(s)
- Suk Yee Lam
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Michiel C Mommersteeg
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Bingting Yu
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Linda Broer
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Fabian Frost
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Stefan Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ben Schöttker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Yan Zhang
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - Hannah Stocker
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany
| | - Daniel Levy
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - Shih-Jen Hwang
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
| | - Alexis C Wood
- USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | - Russell P Tracy
- Laboratory for Clinical Biochemistry Research, University of Vermont College of Medicine, Colchester, Vermont, USA
| | | | - Marcis Leja
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Janis Klovins
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - Raitis Peculis
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - Dace Rudzite
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | | | - Girts Skenders
- Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia
| | - Vita Rovite
- Latvian Biomedical Research and Study Center, Riga, Latvia
| | - André Uitterlinden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
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27
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Gakis G, Perner S, Stenzl A, Renninger M. The role of single-nucleotide polymorphisms of the 8q24 chromosome region in patients with concomitant bladder and prostate cancer. Scand J Urol 2022; 56:126-130. [PMID: 35274594 DOI: 10.1080/21681805.2022.2049362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To assess whether single-nucleotide polymorphisms (SNPs) of the 8q24 chromosome region are associated with recurrence-free survival (RFS) after radical cystoprostatectomy (RC) in patients with concomitant bladder (BC) and prostate cancer (PC). MATERIALS AND METHODS A cohort of thirty-six patients treated with RC and pelvic lymph node dissection and histologically exhibited invasive BC and incidental PC. Using Sanger sequencing, a total of seven SNPs in the androgen-responsive element of the promoter region of the following genes were assessed in tumor-free lymph nodes and correlated with oncological outcomes: PSCA (rs2294008, rs2978974, rs1045531, rs3736001), MYC (rs6983267), FXBO32 (rs7830622), and MIR151A (rs14974929). The median follow-up was 26 months (range: 4-68). RESULTS In a dominant model, patients exhibiting rs2978974 as a minor allelic variant of the PSCA gene had worse RFS (32 vs. 75%, p = 0.015). No associations were found for the other SNPs. CONCLUSIONS These data suggest that the rs2978974 of the PSCA gene correlates with inferior BC-specific RFS after RC and should be further evaluated in larger studies.
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Affiliation(s)
- Georgios Gakis
- Department of Urology and Pediatric Urology, University Hospital of Würzburg, Julius-Maximillians University, Würzburg, Germany
| | - Sven Perner
- Institute of Pathology, University of Luebeck, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.,Department of Pathology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital, Eberhard-Karls University, Tübingen, Germany
| | - Markus Renninger
- Department of Urology, University Hospital, Eberhard-Karls University, Tübingen, Germany
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28
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Akbari A, Ashtari S, Tabaiean SP, Mehrdad‐Majd H, Farsi F, Shojaee S, Agah S. Overview of epidemiological characteristics, clinical features, and risk factors of gastric cancer in Asia‐Pacific region. Asia Pac J Clin Oncol 2022; 18:493-505. [PMID: 35073453 DOI: 10.1111/ajco.13654] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 06/20/2021] [Indexed: 01/01/2023]
Affiliation(s)
- Abolfazl Akbari
- Colorectal Research Center Iran University of Medical Sciences Tehran Iran
| | - Sara Ashtari
- Gastroenterology and Live Diseases Research Center Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Seidamir Pasha Tabaiean
- Colorectal Research Center Iran University of Medical Sciences Tehran Iran
- Department of Internal Medicine School of Medicine Iran University of Medical Sciences Tehran Iran
| | - Hassan Mehrdad‐Majd
- Cancer Molecular Pathology Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Farnaz Farsi
- Department of Nutrition School of public health Iran University of Medical Sciences Tehran Iran
| | - Sajad Shojaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Shahram Agah
- Colorectal Research Center Iran University of Medical Sciences Tehran Iran
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29
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Shin CM, Park K, Kim N, Won S, Ohn JH, Lee S, Park JH, Kang SJ, Kim JS, Lee DH. rs2671655 single nucleotide polymorphism modulates the risk for gastric cancer in Helicobacter pylori-infected individuals: a genome-wide association study in the Korean population. Gastric Cancer 2022; 25:573-585. [PMID: 35325318 PMCID: PMC8943788 DOI: 10.1007/s10120-022-01285-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 02/04/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To identify genetic variations which is associated with gastric cancer (GC) risk according to Helicobacter pylori infection. METHODS This study incorporated 527 GC patients and 441 controls from a cohort at Seoul National University Bundang Hospital. The associations between GC risk and single nucleotide polymorphisms were calculated, stratified by H. pylori status, adjusting for age, sex, and smoking. mRNA expression from non-cancerous gastric mucosae was evaluated using reverse transcription quantitative polymerase chain reaction. RESULTS In the entire cohort, genome-wide association study showed no significant variants reached the genome-wide significance level. In the H. pylori-positive group, rs2671655 (chr17:47,468,020;hg19, GH17J049387 enhancer region) was identified at a genome-wide significance level, which was more pronounced in diffuse type GC. There was no significant variant in the H. pylori-negative group, indicating the effect modification of rs2671655 by H. pylori. Among the target genes of GH17J049387 enhancer (PHB1, ZNF652 and SPOP), PHB1 mRNA was expressed more in cases than in controls, who were not affected by H. pylori. By contrast, an increase in ZNF652 and SPOP in GC was observed only in the H. pylori-negative group (P < 0.05). Mediation analysis showed that PHB1 (P = 0.0238) and SPOP (P = 0.0328) mediated the effect of rs2671655 on GC risk. The polygenic risk score was associated with the number of rs2671655 risk alleles only in the H. pylori-positive group (P = 0.0112). CONCLUSION After H. pylori infection, rs2671655 may increase GC risk, especially in diffuse-type GC, by regulating the expression of several genes that consequently modify susceptibility to GC.
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Affiliation(s)
- Cheol Min Shin
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea
| | - Kyungtaek Park
- grid.31501.360000 0004 0470 5905Interdisciplinary Program of Bioinformatics, Seoul National University, Seoul, Korea
| | - Nayoung Kim
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea ,grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Sungho Won
- grid.31501.360000 0004 0470 5905Interdisciplinary Program of Bioinformatics, Seoul National University, Seoul, Korea ,grid.31501.360000 0004 0470 5905Department of Public Health Sciences, Seoul National University, Seoul, South Korea
| | - Jung Hun Ohn
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea
| | - Sejoon Lee
- grid.412480.b0000 0004 0647 3378Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Ji Hyun Park
- grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung Joo Kang
- grid.412484.f0000 0001 0302 820XDepartment of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
| | - Joo Sung Kim
- grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea ,grid.412484.f0000 0001 0302 820XDepartment of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
| | - Dong Ho Lee
- grid.412480.b0000 0004 0647 3378Department of Internal Medicine, Seoul National University Bundang Hospital,, 173-82, Gumi-ro, Bundang-gu, Seongnam, Gyeonggi-do 13620 South Korea ,grid.31501.360000 0004 0470 5905Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
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30
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Zheng Y, Lei T, Jin G, Guo H, Zhang N, Chai J, Xie M, Xu Y, Wang T, Liu J, Shen Y, Song Y, Wang B, Yu J, Yang M. LncPSCA in the 8q24.3 risk locus drives gastric cancer through destabilizing DDX5. EMBO Rep 2021; 22:e52707. [PMID: 34472665 DOI: 10.15252/embr.202152707] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 08/16/2021] [Accepted: 08/19/2021] [Indexed: 12/23/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified multiple gastric cancer risk loci and several protein-coding susceptibility genes. However, the role of long-noncoding RNAs (lncRNAs) transcribed from these risk loci in gastric cancer development and progression remains to be explored. Here, we functionally characterize a lncRNA, lncPSCA, as a novel tumor suppressor whose expression is fine-regulated by a gastric cancer risk-associated genetic variant. The rs2978980 T > G change in an intronic enhancer of lncPSCA interrupts binding of transcription factor RORA, which down-regulates lncPSCA expression in an allele-specific manner. LncPSCA interacts with DDX5 and promotes DDX5 degradation through ubiquitination. Increased expression of lncPSCA results in low levels of DDX5, less RNA polymerase II (Pol II) binding with DDX5 in the nucleus, thus activating transcription of multiple p53 signaling genes by Pol II. These findings highlight the importance of functionally annotating lncRNAs in GWAS risk loci and the great potential of modulating lncRNAs as innovative cancer therapy.
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Affiliation(s)
- Yan Zheng
- Research Center of Translational Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China.,Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.,Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tianshui Lei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haiyang Guo
- Clinical Laboratory, Tumor Marker Detection Engineering Laboratory of Shandong Province, The Second Hospital of Shandong University, Jinan, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Mengyu Xie
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yeyang Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Tianpei Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiandong Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yue Shen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yemei Song
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Bowen Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
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31
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Risk Prediction for Gastric Cancer Using GWAS-Identifie Polymorphisms, Helicobacter pylori Infection and Lifestyle-Related Risk Factors in a Japanese Population. Cancers (Basel) 2021; 13:cancers13215525. [PMID: 34771687 PMCID: PMC8583059 DOI: 10.3390/cancers13215525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/27/2021] [Accepted: 10/30/2021] [Indexed: 11/18/2022] Open
Abstract
Simple Summary Gastric cancer remains the major cancer in Japan and worldwide. It is expected that practical intervention strategies for prevention, such as personalized approaches based on genetic risk models, will be developed. Here, we developed and validated a risk prediction model for gastric cancer using genetic, biological, and lifestyle-related risk factors. Results showed that the combination of selected GWAS-identified SNP polymorphisms and other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies; however, the contribution of genetic factors to risk prediction was limited. The greatest contributor to risk prediction was ABCD classification (Helicobacter pylori infection-related factor). Abstract Background: As part of our efforts to develop practical intervention applications for cancer prevention, we investigated a risk prediction model for gastric cancer based on genetic, biological, and lifestyle-related risk factors. Methods: We conducted two independent age- and sex-matched case–control studies, the first for model derivation (696 cases and 1392 controls) and the second (795 and 795) for external validation. Using the derivation study data, we developed a prediction model by fitting a conditional logistic regression model using the predictors age, ABCD classification defined by H. pylori infection and gastric atrophy, smoking, alcohol consumption, fruit and vegetable intake, and 3 GWAS-identified polymorphisms. Performance was assessed with regard to discrimination (area under the curve (AUC)) and calibration (calibration plots and Hosmer–Lemeshow test). Results: A combination of selected GWAS-identified polymorphisms and the other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies, with AUCs of 0.77 (95% confidence intervals: 0.75–0.79) and 0.78 (0.77–0.81), respectively. The calibration plots of both studies stayed close to the ideal calibration line. In the validation study, the environmental model (nongenetic model) was significantly more discriminative than the inclusive model, with an AUC value of 0.80 (0.77–0.82). Conclusion: The contribution of genetic factors to risk prediction was limited, and the ABCD classification (H. pylori infection-related factor) contributes most to risk prediction of gastric cancer.
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Miller AK, Tavera G, Dominguez RL, Camargo MC, Waterboer T, Wilson KT, Williams SM, Morgan DR. Ornithine decarboxylase (ODC1) gene variant (rs2302615) is associated with gastric cancer independently of Helicobacter pylori CagA serostatus. Oncogene 2021; 40:5963-5969. [PMID: 34376808 PMCID: PMC8692072 DOI: 10.1038/s41388-021-01981-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 07/08/2021] [Accepted: 07/22/2021] [Indexed: 02/07/2023]
Abstract
The primary cause of gastric cancer is chronic infection with Helicobacter pylori (H. pylori), particularly the high-risk genotype cagA, and risk modification by human genetic variants. We studied 94 variants in 54 genes for association with gastric cancer, including rs2302615 in ornithine decarboxylase (ODC1), which may affect response to chemoprevention with the ODC inhibitor, eflornithine (difluoromethylornithine; DFMO). Our population-based, case-control study included 1366 individuals (664 gastric cancer cases and 702 controls) from Western Honduras, a high incidence region of Latin America. CagA seropositivity was strongly associated with cancer (OR = 3.6; 95% CI: 2.6, 5.1). The ODC1 variant rs2302615 was associated with gastric cancer (OR = 1.36; p = 0.018) in a model adjusted for age, sex, and CagA serostatus. Two additional single nucleotide polymorphisms (SNPs) in CASP1 (rs530537) and TLR4 (rs1927914) genes were also associated with gastric cancer in univariate models as well as models adjusted for age, sex, and CagA serostatus. The ODC1 SNP association with gastric cancer was stronger in individuals who carried the TT genotype at the associating TLR4 polymorphism, rs1927914 (OR = 1.77; p = 1.85 × 10-3). In conclusion, the ODC1 variant, rs2302615, is associated with gastric cancer and supports chemoprevention trials with DFMO, particularly in individuals homozygous for the T allele at rs1927914.
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Affiliation(s)
- Anna K Miller
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Gloria Tavera
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Ricardo L Dominguez
- Hospital de Occidente, Ministry of Health, Santa Rosa de Copan, Copan, Honduras
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Keith T Wilson
- Vanderbilt University Medical Center, Division of Gastroenterology, Hepatology, and Nutrition, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Scott M Williams
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
| | - Douglas R Morgan
- UAB Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
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Nguyen NLT, Dang NDT, Dang QH, Tran VC, Vo HL, Yamaguchi M, Ta TV. Polymorphism of MUC1 Gene in Vietnamese Gastric Cancer Patients: A Multicenter Case-Control Study. Front Oncol 2021; 11:694977. [PMID: 34532288 PMCID: PMC8439541 DOI: 10.3389/fonc.2021.694977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/10/2021] [Indexed: 12/31/2022] Open
Abstract
Background A few studies revealed that the polymorphisms of Mucin 1 gene have a role and significance as a susceptible factor contributing to gastric cancer. To better understand the roles of two MUC1 genotype polymorphisms of rs4072037 and rs2070803 in the development of gastric cancer in Vietnamese population, a multicenter, large-sample, case-control study was conducted to investigate the potential association of these single-nucleotide polymorphisms (SNPs) of MUC1 gene with gastric cancer risk and to evaluate the combination factors in relation with these SNPs. Methods This case-control study included 302 gastric cancer patients and 304 controls at four national medical hospitals between 2016 and 2018. All participants were interviewed for sociodemographic characteristics, smoking and drinking status, and personal and family history of gastric diseases. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism analysis. The association of SNPs with gastric cancer was explored using logistic regression models. Results AA genotype for rs4072037 was significantly associated with increased gastric cancer. Those with AA genotype had higher gastric cancer risk than had patients with AG (OR: 2.09, 95% CI: 1.48-2.96) and a combination of AG+GG (OR: 1.85, 95% CI: 1.33-2.56). In rs2070803, GG genotype increased gastric cancer risk when compared with AG (OR: 1.97, 95% CI: 1.39-2.80) and AG+AA (OR: 1.71, 95% CI: 1.23-2.39). AG genotypes in both SNPs decreased gastric cancer risk when compared with homogenous genotype, more specifically AA (OR: 0.51, 95% CI: 0.35-0.72) and GG (OR: 0.58, 95% CI: 0.35-0.97). These genotypes in combination with above-60-year-old age, male gender, alcoholism, and personal history of gastric disease were also significantly elevated risk factors for gastric cancer. Conclusions rs4072037 and rs2070803 of Mucin 1 genes are two genotypic risk factors for gastric cancer. Those in combination with gender, family history, smoking, and drinking habits significantly increase the risk of gastric cancer.
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Affiliation(s)
- Ngoc-Lan Thi Nguyen
- Biochemistry Department, Hanoi Medical University, Hanoi, Vietnam.,Clinical Laboratory, Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam
| | - Ngoc-Dzung Thi Dang
- Biochemistry Department, Hanoi Medical University, Hanoi, Vietnam.,Clinical Laboratory, Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam
| | - Quang-Huy Dang
- Department of Medical Laboratory Science, Faculty of Medical Technology, Hanoi Medical University, Hanoi, Vietnam
| | - Van-Chuc Tran
- Biochemistry Department, Hanoi Medical University, Hanoi, Vietnam
| | - Hoang-Long Vo
- Department of Scientific Research and International Cooperation, Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam
| | - Masamitsu Yamaguchi
- Department of Applied Biology, Advanced Insect Research Promotion Center, Kyoto Institute of Technology, Kyoto, Japan
| | - Thanh-Van Ta
- Biochemistry Department, Hanoi Medical University, Hanoi, Vietnam.,Clinical Laboratory, Hanoi Medical University Hospital, Hanoi Medical University, Hanoi, Vietnam
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Duan F, Song C, Shi J, Wang P, Ye H, Dai L, Zhang J, Wang K. Identification and epidemiological evaluation of gastric cancer risk factors: based on a field synopsis and meta-analysis in Chinese population. Aging (Albany NY) 2021; 13:21451-21469. [PMID: 34491229 PMCID: PMC8457565 DOI: 10.18632/aging.203484] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 08/11/2021] [Indexed: 12/16/2022]
Abstract
To summarize and assess the credibility and strength of non-genetic factors and genetic variation on gastric cancer risk, we performed a field synopsis and meta-analysis to identify the risk of gastric cancer in Chinese population. Cumulative evidence was graded according to the Venice criteria, and attributable risk percentage (ARP) and population attributable risk percentage (PARP) were used to evaluate the epidemiological effect. A total of 956 studies included non-genetic (404 studies) and genetic factors (552 studies) were quantified, and data on 1161 single nucleotide polymorphisms (SNPs) were available. We identified 14 non-genetic factors were significantly associated with gastric cancer risk. For the analysis of time trends, H. pylori infection rate in gastric cancer and population showed a downward trend. Meanwhile 22 variants were identified significantly associated with gastric cancer: 3 (PLCE1 rs2274223, PSCA rs2976392, MUC1 rs4072037) were high and 19 SNPs were intermediate level of summary evidence, respectively. For non-genetic factors, the top three for ARP were 54.75% (pickled food), 65.87% (stomach disease), and 49.75% (smoked and frying). For PARP were 34.22% (pickled food), 34.24% (edible hot food) and 23.66%(H. pylori infection). On the basis of ARP and PARP associated with SNPs of gastric cancer, the top three for ARP were 53.91% (NAT2, rs1799929),53.05% (NAT2 phenotype), and 42.85% (IL-10, rs1800896). For PARP (Chinese Han in Beijing) were 36.96% (VDR, rs731236), 25.58% (TGFBR2, rs3773651) and 20.56% (MUC1, rs4072037). Our study identified non-genetic risk factors and high-quality biomarkers of gastric cancer susceptibility and their contribution to gastric cancer.
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Affiliation(s)
- Fujiao Duan
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou, Henan Province, China.,Medical Research Office, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Chunhua Song
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou, Henan Province, China
| | - Jiachen Shi
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University,Zhengzhou, Henan Province, China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou, Henan Province, China
| | - Hua Ye
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou, Henan Province, China
| | - Liping Dai
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou, Henan Province, China
| | - Jianying Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou, Henan Province, China
| | - Kaijuan Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.,Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou, Henan Province, China
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Miller AK, Williams SM. Helicobacter pylori infection causes both protective and deleterious effects in human health and disease. Genes Immun 2021; 22:218-226. [PMID: 34244666 PMCID: PMC8390445 DOI: 10.1038/s41435-021-00146-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023]
Abstract
Infection with Helicobacter pylori (H. pylori) is necessary but not sufficient for the development of gastric cancer, the third leading cause of cancer death globally. H. pylori infection affects over half of people globally; however, it does not affect populations uniformly. H. pylori infection rates are declining in western industrialized countries but are plateauing in developing and newly industrialized countries where gastric cancer is most prevalent. Despite H. pylori infection being the primary causative agent for gastric cancer, H. pylori infection can also cause other effects, detrimental or beneficial, throughout an individual's life, with the beneficial effects often being seen in childhood and the deleterious effects in adulthood. H. pylori is an ancient bacterium and its likelihood of affecting disease or health is dependent on both human and bacterial genetics that have co-evolved over millennia. In this review, we focus on the impact of infection and its genetic bases in different populations and diseases throughout an individual's lifespan, highlighting the benefits of individualized treatment and argue that universal eradication of H. pylori in its host may cause more harm than good for those infected with H. pylori.
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Affiliation(s)
- Anna K Miller
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH
| | - Scott M Williams
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH,Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
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Geospatial Assessments of DNA Adducts in the Human Stomach: A Model of Field Cancerization. Cancers (Basel) 2021; 13:cancers13153728. [PMID: 34359626 PMCID: PMC8345122 DOI: 10.3390/cancers13153728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Field cancerization is a popular concept regarding where cancer cells arise in a plane, such as the opened-up gastrointestinal mucosa. The geospatial distribution of DNA adducts, some of which are believed to initiate mutation, may be a clue to understanding the landscape of the preferred occurrence of gastric cancer in the human stomach, such that the occurrence is much more frequent in the lesser curvature than in the greater curvature. METHODS Seven DNA adducts, C5-methyl-2'-deoxycytidine, 2'-deoxyinosine, C5-hydroxymethyl-2'-deoxycytidine, N6-methyl-2'-deoxyadenosine, 1,N6-etheno-2'-deoxyadenosine, N6-hydroxymethyl-2'-deoxyadenosine, and C8-oxo-2'-deoxyguanosine, from different points and zones of the human stomach were semi quantitatively measured by liquid chromatography/tandem mass spectrometry. The differences in the quantity of these DNA adducts from the lesser and greater curvature, the upper, middle and lower third zones, the anterior and posterior wall of the stomach, and the mucosae distant from and near the tumor were compared to determine whether the location preference of cancer in the stomach could be explained by the distribution of these DNA adducts. Comparisons were conducted considering the tumor locations and operation methods. CONCLUSIONS Regarding the DNA adducts investigated, significant differences in quantities and locations in the whole stomach were not noted; thus, these DNA adducts do not explain the preferential occurrence of cancer in particular locations of the human stomach.
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Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations. J Hum Genet 2021; 66:887-899. [PMID: 34267306 PMCID: PMC8384627 DOI: 10.1038/s10038-021-00960-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/08/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
The prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming "H. pylori-negative era."
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Zhou J, Liu J, Xing H, Shen Y, Xie M, Chai J, Yang M. Implications of protein ubiquitination modulated by lncRNAs in gastrointestinal cancers. Biochem Pharmacol 2021; 188:114558. [PMID: 33844983 DOI: 10.1016/j.bcp.2021.114558] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 04/03/2021] [Accepted: 04/06/2021] [Indexed: 02/05/2023]
Abstract
Long non-coding RNAs (lncRNAs) are a class of RNA transcripts longer than 200 nucleotides and mostly cannot be translated into proteins. Next-generation transcriptome sequencing of various cell types has enabled the annotation of tens of thousands of lncRNAs in human genome. Varying levels of evidence supports the implications of lncRNAs in the onset and progression of cancers. Ubiquitin is an evolutionarily conserved protein and could post-translationally mark a number of proteins. The most important proteolytic role of ubiquitination is degradation of substrate proteins by the 26S proteasome. Compiling evidences demonstrated that lncRNAs are involved in the accurate execution of protein stability programs via the ubiquitin-proteasome system. In the current review, we systematically summarize the detailed mechanisms how lncRNAs modulate ubiquitination of target proteins, regulate cancerous signaling pathways and control tumorigenesis of gastrointestinal cancers. Although there are still considerable studies on unraveling the complicated interactions between lncRNAs and proteins, we believe that lncRNAs are promising but challenging molecules which may strongly facilitate precision cancer therapeutics in the future.
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Affiliation(s)
- Jianyuan Zhou
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Jie Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Huaixin Xing
- Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Yue Shen
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Mengyu Xie
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Chai
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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Toyoshima O, Nishizawa T, Yoshida S, Aoki T, Nagura F, Sakitani K, Tsuji Y, Nakagawa H, Suzuki H, Koike K. Comparison of endoscopic gastritis based on Kyoto classification between diffuse and intestinal gastric cancer. World J Gastrointest Endosc 2021; 13:125-136. [PMID: 34046150 PMCID: PMC8134854 DOI: 10.4253/wjge.v13.i5.125] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/14/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancers can be categorized into diffuse- and intestinal-type cancers based on the Lauren histopathological classification. These two subtypes show distinct differences in metastasis frequency, treatment application, and prognosis. Therefore, accurately assessing the Lauren classification before treatment is crucial. However, studies on the gastritis endoscopy-based Kyoto classification have recently shown that endoscopic diagnosis has improved.
AIM To investigate patient characteristics including endoscopic gastritis associated with diffuse- and intestinal-type gastric cancers in Helicobacter pylori (H. pylori)-infected patients.
METHODS Patients who underwent esophagogastroduodenoscopy at the Toyoshima Endoscopy Clinic were enrolled. The Kyoto classification included atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. The effects of age, sex, and Kyoto classification score on gastric cancer according to the Lauren classification were analyzed. We developed the Lauren predictive background score based on the coefficients of a logistic regression model using variables independently associated with the Lauren classification. Area under the receiver operative characteristic curve and diagnostic accuracy of this score were examined.
RESULTS A total of 499 H. pylori-infected patients (49.6% males; average age: 54.9 years) were enrolled; 132 patients with gastric cancer (39 diffuse- and 93 intestinal-type cancers) and 367 cancer-free controls were eligible. Gastric cancer was independently associated with age ≥ 65 years, high atrophy score, high intestinal metaplasia score, and low nodularity score when compared to the control. Factors independently associated with intestinal-type cancer were age ≥ 65 years (coefficient: 1.98), male sex (coefficient: 1.02), high intestinal metaplasia score (coefficient: 0.68), and low enlarged folds score (coefficient: -1.31) when compared to diffuse-type cancer. The Lauren predictive background score was defined as the sum of +2 (age ≥ 65 years), +1 (male sex), +1 (endoscopic intestinal metaplasia), and -1 (endoscopic enlarged folds) points. Area under the receiver operative characteristic curve of the Lauren predictive background score was 0.828 for predicting intestinal-type cancer. With a cut-off value of +2, the sensitivity, specificity, and accuracy of the Lauren predictive background score were 81.7%, 71.8%, and 78.8%, respectively.
CONCLUSION Patient backgrounds, such as age, sex, endoscopic intestinal metaplasia, and endoscopic enlarged folds are useful for predicting the Lauren type of gastric cancer.
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Affiliation(s)
- Osamu Toyoshima
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 157-0066, Japan
| | - Toshihiro Nishizawa
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 157-0066, Japan
- Department of Gastroenterology and Hepatology, International University of Health and Welfare, Narita Hospital, Narita 286-8520, Japan
| | - Shuntaro Yoshida
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 157-0066, Japan
| | - Tomonori Aoki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Fumiko Nagura
- Internal Medicine, Chitosefunabashi Ekimae Clinic, Tokyo 157-0054, Japan
| | - Kosuke Sakitani
- Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 157-0066, Japan
- Department of Gastroenterology, Sakiatani Endoscopy Clinic, Narashino 275-0026, Japan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Hidekazu Suzuki
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
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Dixon K, Brew T, Farnell D, Godwin TD, Cheung S, Chow C, Ta M, Ho G, Bui M, Douglas JM, Campbell KR, El-Naggar A, Kaurah P, Kalloger SE, Lim HJ, Schaeffer DF, Cochrane D, Guilford P, Huntsman DG. Modelling hereditary diffuse gastric cancer initiation using transgenic mouse-derived gastric organoids and single-cell sequencing. J Pathol 2021; 254:254-264. [PMID: 33797756 DOI: 10.1002/path.5675] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/02/2021] [Accepted: 03/30/2021] [Indexed: 12/11/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome caused by germline variants in CDH1, the gene encoding the cell-cell adhesion molecule E-cadherin. Loss of E-cadherin in cancer is associated with cellular dedifferentiation and poor prognosis, but the mechanisms through which CDH1 loss initiates HDGC are not known. Using single-cell RNA sequencing, we explored the transcriptional landscape of a murine organoid model of HDGC to characterize the impact of CDH1 loss in early tumourigenesis. Progenitor populations of stratified squamous and simple columnar epithelium, characteristic of the mouse stomach, showed lineage-specific transcriptional programs. Cdh1 inactivation resulted in shifts along the squamous differentiation trajectory associated with aberrant expression of genes central to gastrointestinal epithelial differentiation. Cytokeratin 7 (CK7), encoded by the differentiation-dependent gene Krt7, was a specific marker for early neoplastic lesions in CDH1 carriers. Our findings suggest that deregulation of developmental transcriptional programs may precede malignancy in HDGC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Katherine Dixon
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
| | - Tom Brew
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - David Farnell
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
| | - Tanis D Godwin
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Simon Cheung
- Division of Anatomic Pathology, Vancouver Coastal Health, Vancouver, Canada
| | - Christine Chow
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, Canada
| | - Monica Ta
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, Canada
| | - Germain Ho
- Department of Molecular Oncology, BC Cancer, Vancouver, Canada
| | - Minh Bui
- Department of Molecular Oncology, BC Cancer, Vancouver, Canada
| | | | | | - Amal El-Naggar
- Department of Molecular Oncology, BC Cancer, Vancouver, Canada.,Department of Pathology, Menoufia University, Shibin El Kom, Egypt
| | | | - Steve E Kalloger
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
| | - Howard J Lim
- Department of Medical Oncology, BC Cancer, Vancouver, Canada
| | - David F Schaeffer
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.,Division of Anatomic Pathology, Vancouver Coastal Health, Vancouver, Canada
| | - Dawn Cochrane
- Department of Molecular Oncology, BC Cancer, Vancouver, Canada
| | - Parry Guilford
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - David G Huntsman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
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Bhat A, Bhat GR, Verma S, Sharma B, Bakshi D, Abrol D, Singh S, Qadri RA, Shah R, Kumar R. Evaluation of 17 genetic variants in association with leukemia in the north Indian population using MassARRAY Sequenom. J Biochem Mol Toxicol 2021; 35:e22792. [PMID: 33928715 DOI: 10.1002/jbt.22792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/29/2021] [Accepted: 04/08/2021] [Indexed: 12/24/2022]
Abstract
Leukemia is a heterogeneous disorder, characterized by elevated proliferation of white blood cells. In this study, we explored the association of 17 genetic variants with leukemia patients in the Jammu and Kashmir region of north India. The variants were genotyped by using a high-throughput Agena MassARRAY platform in 758 individuals (166 cases and 592 controls). Of the 17 single-nucleotide polymorphisms (SNPs) studied, five SNPs were showing significant association with the high risk of leukemia in the north Indian population, which includes rs10069690 of telomere reverse transcriptase (TERT) with OR = 0.34 (95% CI, 0.20-0.58; p = .0008), rs2972392 (PSCA) with OR 1.86 (95% CI, 1.04-3.81; p = .035), rs4986764 (BRIP1) with OR 1.34 (95% CI, 1.00-1.80; p = .04), rs6990097 (TNKS) with OR 1.81 (95% CI, 1.2-2.6; p = .001) and rs12190287 (TCF21) with OR 2.87 (95% CI, 1.72-4.7; p = .0001) by allelic association using Plink and analyzed by SPSS. This is the first study to explore these variants with leukemia in the studied population.
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Affiliation(s)
- Amrita Bhat
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
| | - Gh Rasool Bhat
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
| | - Sonali Verma
- ICMR-CAR, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
| | - Bhanu Sharma
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
| | - Divya Bakshi
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
| | - Deepak Abrol
- Department of Radiotherapy, Government Medical College Kathua, Jammu and Kashmir, India
| | - Supinder Singh
- Department of Medicine, ASCOMS, Sidhra, Jammu and Kashmir, India
| | | | - Ruchi Shah
- ICMR-CAR, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Rakesh Kumar
- Cancer Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
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Zhang G, Xue Z, Yan C, Wang J, Luo H. A Novel Biomarker Identification Approach for Gastric Cancer Using Gene Expression and DNA Methylation Dataset. Front Genet 2021; 12:644378. [PMID: 33868380 PMCID: PMC8044773 DOI: 10.3389/fgene.2021.644378] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/16/2021] [Indexed: 01/09/2023] Open
Abstract
As one type of complex disease, gastric cancer has high mortality rate, and there are few effective treatments for patients in advanced stage. With the development of biological technology, a large amount of multiple-omics data of gastric cancer are generated, which enables computational method to discover potential biomarkers of gastric cancer. That will be very important to detect gastric cancer at earlier stages and thus assist in providing timely treatment. However, most of biological data have the characteristics of high dimension and low sample size. It is hard to process directly without feature selection. Besides, only using some omic data, such as gene expression data, provides limited evidence to investigate gastric cancer associated biomarkers. In this research, gene expression data and DNA methylation data are integrated to analyze gastric cancer, and a feature selection approach is proposed to identify the possible biomarkers of gastric cancer. After the original data are pre-processed, the mutual information (MI) is applied to select some top genes. Then, fold change (FC) and T-test are adopted to identify differentially expressed genes (DEG). In particular, false discover rate (FDR) is introduced to revise p_value to further screen genes. For chosen genes, a deep neural network (DNN) model is utilized as the classifier to measure the quality of classification. The experimental results show that the approach can achieve superior performance in terms of accuracy and other metrics. Biological analysis for chosen genes further validates the effectiveness of the approach.
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Affiliation(s)
- Ge Zhang
- School of Computer and Information Engineering, Henan University, Kaifeng, China
| | - Zijing Xue
- School of Computer and Information Engineering, Henan University, Kaifeng, China
| | - Chaokun Yan
- School of Computer and Information Engineering, Henan University, Kaifeng, China
| | - Jianlin Wang
- School of Computer and Information Engineering, Henan University, Kaifeng, China
| | - Huimin Luo
- School of Computer and Information Engineering, Henan University, Kaifeng, China
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Yan LR, Lv Z, Jing JJ, Yuan Y, Xu Q. Single nucleotide polymorphisms of whole genes and atrophic gastritis susceptibility:a systematic review and meta-analysis. Gene 2021; 782:145543. [PMID: 33667608 DOI: 10.1016/j.gene.2021.145543] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/29/2021] [Accepted: 02/18/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Atrophic gastritis (AG) is one of the important precancerous lesions of gastric cancer. Single nucleotide polymorphisms (SNPs) are closely related to AG susceptibility. However, the research conclusions on the predictive potential of SNPs are inconsistent. The study aims to retrospect the association between SNPs of whole genes and AG risk by meta-analysis. MATERIALS AND METHODS Up to April 29, 2020, a systematic literature search for the relationship of SNPs with AG susceptibility was performed utilizing PubMed, Web of Science and Chinese National Knowledge Infrastructure. The overall and stratified meta-analyses on extracted data were conducted by Stata11.2. RESULTS 33 case-control studies were enrolled containing 9951 AG patients and 17,252 healthy controls, and 17 SNPs in 12 different genes were systematically reviewed. The results indicated that 12 genes could be categorized based on their functions, including immune response, cell proliferation and apoptosis, and DNA damage repair. For the SNPs in immune response-related genes, the C allele of TLR1 rs4833095 T/C increased AG risk to 1.21-fold and the recessive model of TLR4 rs11536878 in the TLR gene family decreased AG susceptibility to 0.48-fold. The variant alleles of IL-10 rs1800871 (OR = 1.21) and IL-8 rs4073 (OR = 1.22) in the IL gene family were positively associated with AG risk. PSCA rs2294008 enhanced AG risk in all genetic models. SNPs associated with AG susceptibility were mainly focused on immune response-related genes. CONCLUSION These SNPs related to immune response could influence on AG risk and have potential to be AG predictive biomarkers. It is worth noting that the number of studies for each SNPs were insufficient due to the limited published researches and updated meta-analysis needs to be performed based on extensive relevant studies for more reliable results.
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Affiliation(s)
- Li-Rong Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China
| | - Zhi Lv
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jing-Jing Jing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China.
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China.
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Usui Y, Matsuo K, Oze I, Ugai T, Koyanagi Y, Maeda Y, Ito H, Hishida A, Takeuchi K, Tamura T, Tsukamoto M, Kadomatsu Y, Hara M, Nishida Y, Shimoshikiryo I, Takezaki T, Ozaki E, Matsui D, Watanabe I, Suzuki S, Watanabe M, Nakagawa-Senda H, Mikami H, Nakamura Y, Arisawa K, Uemura H, Kuriki K, Takashima N, Kadota A, Ikezaki H, Murata M, Nakatochi M, Momozawa Y, Kubo M, Wakai K. Impact of PSCA Polymorphisms on the Risk of Duodenal Ulcer. J Epidemiol 2021; 31:12-20. [PMID: 31839644 PMCID: PMC7738644 DOI: 10.2188/jea.je20190184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 11/22/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND While duodenal ulcer (DU) and gastric cancer (GC) are both H. pylori infection-related diseases, individuals with DU are known to have lower risk for GC. Many epidemiological studies have identified the PSCA rs2294008 T-allele as a risk factor of GC, while others have found an association between the rs2294008 C-allele and risk of DU and gastric ulcer (GU). Following these initial reports, however, few studies have since validated these associations. Here, we aimed to validate the association between variations in PSCA and the risk of DU/GU and evaluate its interaction with environmental factors in a Japanese population. METHODS Six PSCA SNPs were genotyped in 584 DU cases, 925 GU cases, and 8,105 controls from the Japan Multi-Institutional Collaborative Cohort (J-MICC). Unconditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the SNPs and risk of DU/GU. RESULTS PSCA rs2294008 C-allele was associated with per allele OR of 1.34 (95% CI, 1.18-1.51; P = 2.28 × 10-6) for the risk of DU. This association was independent of age, sex, study site, smoking habit, drinking habit, and H. pylori status. On the other hand, we did not observe an association between the risk of GU and PSCA SNPs. CONCLUSIONS Our study confirms an association between the PSCA rs2294008 C-allele and the risk of DU in a Japanese population.
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Affiliation(s)
- Yoshiaki Usui
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceuticals Sciences, Okayama, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Isao Oze
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
| | - Tomotaka Ugai
- Division of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
| | - Yuriko Koyanagi
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
| | - Yoshinobu Maeda
- Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceuticals Sciences, Okayama, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center, Nagoya, Japan
- Division of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Takeuchi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Tamura
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mineko Tsukamoto
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuka Kadomatsu
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Megumi Hara
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuichiro Nishida
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Ippei Shimoshikiryo
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Toshiro Takezaki
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Etsuko Ozaki
- Department of Epidemiology for Community Health and Medicine Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Daisuke Matsui
- Department of Epidemiology for Community Health and Medicine Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Isao Watanabe
- Department of Epidemiology for Community Health and Medicine Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Miki Watanabe
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroko Nakagawa-Senda
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Haruo Mikami
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Yohko Nakamura
- Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Kokichi Arisawa
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hirokazu Uemura
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Kiyonori Kuriki
- Laboratory of Public Health, University of Shizuoka, Shizuoka, Japan
| | - Naoyuki Takashima
- Department of Public Health, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Aya Kadota
- Department of Public Health, Shiga University of Medical Science, Otsu, Japan
| | - Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masahiro Nakatochi
- Department of Nursing, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Michiaki Kubo
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Toyoshima O, Nishizawa T, Sekiba K, Matsuno T, Kondo R, Watanabe H, Suzuki H, Tanikawa C, Koike K, Matsuda K. A single nucleotide polymorphism in Prostate Stem Cell Antigen is associated with endoscopic grading in Kyoto classification of gastritis. J Clin Biochem Nutr 2021; 68:73-77. [PMID: 33536715 PMCID: PMC7844668 DOI: 10.3164/jcbn.20-67] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 05/09/2020] [Indexed: 12/13/2022] Open
Abstract
The risk allele of a single nucleotide polymorphism (SNP) rs2294008 in the Prostate stem cell antigen (PSCA) gene is strongly associated with gastric cancer. Although the Kyoto classification score is believed to be an indicator of gastric cancer risk, it lacks supporting genetic evidence. We investigated the effect of this risk allele of PSCA SNP on the Kyoto score. Participants without a history of gastric cancer or Helicobacter pylori (H. pylori) eradication underwent esophagogastroduodenoscopy, H. pylori evaluation, and SNP genotyping. The Kyoto score is the sum of scores obtained from endoscopy-based atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. The Kyoto score is novel in the light of scoring for gastritis. A total of 323 patients were enrolled (number of individuals with genotype CC: 52; CT: 140; TT: 131, average age: 50.1 years, male: 50.8%). The patient baseline characteristics including age, sex, body mass index, smoking, drinking, family history of gastric cancer, and H. pylori status had no association with PSCA SNP. The Kyoto score was higher in T (CT or TT genotype; risk allele) carriers than in CC carriers. Atrophy, enlarged folds, and diffuse redness scores were higher in T allele carriers (risk allele) than in CC genotype individuals. In multivariate analysis, the Kyoto score was independently associated with PSCA SNP (OR: 1.30, p = 0.012). Thus, the Kyoto score was associated with a genetic predisposition.
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Affiliation(s)
- Osamu Toyoshima
- Gastroenterology, Toyoshima Endoscopy Clinic, 6-17-5 Seijo, Setagaya, Tokyo 157-0066, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
| | - Toshihiro Nishizawa
- Gastroenterology, Toyoshima Endoscopy Clinic, 6-17-5 Seijo, Setagaya, Tokyo 157-0066, Japan
- Department of Gastroenterology and Hepatology, International University of Health and Welfare, Narita Hospital, 852 Hatakeda, Narita, Chiba 286-8520, Japan
| | - Kazuma Sekiba
- Gastroenterology, Toyoshima Endoscopy Clinic, 6-17-5 Seijo, Setagaya, Tokyo 157-0066, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
| | - Tatsuya Matsuno
- Gastroenterology, Toyoshima Endoscopy Clinic, 6-17-5 Seijo, Setagaya, Tokyo 157-0066, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
| | - Ryo Kondo
- Gastroenterology, Toyoshima Endoscopy Clinic, 6-17-5 Seijo, Setagaya, Tokyo 157-0066, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
| | - Hidenobu Watanabe
- Pathology and Cytology Laboratory Japan, 1-34-5 Koenji-Minami, Suginami, Tokyo 166-0003, Japan
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
| | - Chizu Tanikawa
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
| | - Koichi Matsuda
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033, Japan
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Polymorphisms PSCA rs2294008, IL-4 rs2243250 and MUC1 rs4072037 are associated with gastric cancer in a high risk population. Mol Biol Rep 2020; 47:9239-9243. [PMID: 33128686 DOI: 10.1007/s11033-020-05943-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 10/22/2020] [Indexed: 01/22/2023]
Abstract
Genetic variants are considered risk factors for gastric cancer. To date, 61 polymorphisms have been identified as associated with this disease. The aim of the present study was to analyze the association of some of those polymorphisms with GC in Chile. We performed a case-control study including 310 gastric cancer cases and 311 controls to assess the association of 36 single-nucleotide polymorphisms genotyped by Global Screening Array (GSA). Three polymorphisms was significantly associated: PSCA rs2294008 (allele model, OR = 1.49, 95%CI 1.17-1.88, P = 1.08 × 10-3), IL-4 rs2243250 (allele model, OR = 1.28, 95%CI 1.01-1.62, P = 0.04), and MUC1 rs4072037 (allele model, OR = 0.78, 95%CI 0.61-0.99, P = 0.04).PSCA rs2294008, IL-4 rs2243250 and MUC1 rs4072037 are associated with gastric cancer in Chile. It suggests that those polymorphisms could be used as biomarkers to assess the genetic risk for this cancer outside of the previously studied populations, not only for East Asians and Caucasians populations.
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Qiu L, Qu X, He J, Cheng L, Zhang R, Sun M, Yang Y, Wang J, Wang M, Zhu X, Guo W. Predictive model for risk of gastric cancer using genetic variants from genome-wide association studies and high-evidence meta-analysis. Cancer Med 2020; 9:7310-7316. [PMID: 32777176 PMCID: PMC7541133 DOI: 10.1002/cam4.3354] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 02/05/2023] Open
Abstract
Genome-wide association studies (GWAS) have identified some single nucleotide polymorphisms (SNPs) associated with the risk of gastric cancer (GCa). However, currently, there is no published predictive model to assess the risk of GCa. In the present study, risk-associated SNPs derived from GWAS and large meta-analyses were selected to construct a predictive model to assess the risk of GCa. A total of 1115 GCa cases and 1172 controls from the eastern Chinese population were included. Logistic regression models were used to identify SNPs that correlated with the risk of GCa. A predictive model to assess the risk of GCa was established by receiver operating characteristic curve analysis. Multifactor dimensionality reduction (MDR) and classification and regression tree (CART) were applied to calculate the effect of high-order gene-environment interactions on risk of the cancer. A total of 42 SNPs were selected for further analysis. The results revealed that ASH1L rs80142782, PKLR rs3762272, PRKAA1 rs13361707, MUC1 rs4072037, PSCA rs2294008, and PLCE1 rs2274223 polymorphisms were associated with a risk of GCa. The area under curve considering both genetic factors and BMI was 3.10% higher than that of BMI alone. MDR analysis revealed that rs13361707 and rs4072307 variants and BMI had interaction effects on susceptibility to GCa, with the highest predictive accuracy (61.23%) and cross-validation consistency (100/100). CART analysis also supported this interaction model that non-overweight status and a six SNP panel could synergistically increase the susceptibility to GCa. The six SNP panel for predicting the risk of GCa may provide new tools for prevention of the cancer based on GWAS and large meta-analyses derived genetic variants.
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Affiliation(s)
- Lixin Qiu
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Xiaofei Qu
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Jing He
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Lei Cheng
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Ruoxin Zhang
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Menghong Sun
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
| | - Yajun Yang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic EngineeringSchool of Life SciencesFudan UniversityShanghaiChina
- Fudan‐Taizhou Institute of Health SciencesTaizhouChina
| | - Jiucun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic EngineeringSchool of Life SciencesFudan UniversityShanghaiChina
- Fudan‐Taizhou Institute of Health SciencesTaizhouChina
| | - Mengyun Wang
- Cancer InstituteCollaborative Innovation Center for Cancer MedicineFudan University Shanghai Cancer CenterShanghaiChina
| | - Xiaodong Zhu
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Weijian Guo
- Department of Medical OncologyFudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghaiChina
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Prediction of gastric cancer risk: association between ZBTB20 genetic variance and gastric cancer risk in Chinese Han population. Biosci Rep 2020; 40:226430. [PMID: 32936247 PMCID: PMC7517264 DOI: 10.1042/bsr20202102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/19/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Gastric cancer (GC) is a complex multifactorial disease. Previous studies have revealed genetic variations associated with the risk of gastric cancer. The purpose of the present study was to determine the correlation between single-nucleotide polymorphisms (SNPs) of ZBTB20 and the risk of gastric cancer in Chinese Han population. Methods: We conducted a ‘case–control’ study involving 509 GC patients and 507 healthy individuals. We selected four SNPs of ZBTB20 (10934270 T/C, rs9288999 G/A, rs9841504 G/C and rs73230612 C/T), and used logistic regression to analyze the relationship between those SNPs and GC risk under different genetic models; multi-factor dimensionality reduction (MDR) was used to analyze the interaction of “SNP–SNP” in gastric cancer risk; ANOVA and univariate analysis were used to analyze the differences in clinical characteristics among different genotypes. Results: Our results showed that ZBTB20 rs9288999 is a protective factor for the risk of gastric cancer in multiple genetic models, of which the homozygous model is the most significant (OR = 0.48, P=0.0003); we also found that rs9288999 showed a significant correlation with reducing the risk of gastric cancer in different subgroups (BMI; age; gender; smoking or drinking status; adenocarcinoma); rs9841504 is associated with increased GC risk in the participants with BMI>24 kg/m2; rs9841504 and rs73230612 are certainly associated with clinical characteristics of platelet and carbohydrate antigen 242, respectively. Conclusion: Our results suggest that ZBTB20 rs9288999 may be important for reducing the risk of GC in the Chinese Han population.
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Choi YJ, Ohn JH, Kim N, Kim W, Park K, Won S, Sael L, Shin CM, Lee SM, Lee S, An HJ, Jang DM, Han BW, Lee HS, Kang SJ, Kim JS, Lee DH. Family-based exome sequencing combined with linkage analyses identifies rare susceptibility variants of MUC4 for gastric cancer. PLoS One 2020; 15:e0236197. [PMID: 32701958 PMCID: PMC7377420 DOI: 10.1371/journal.pone.0236197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 06/30/2020] [Indexed: 12/24/2022] Open
Abstract
Genome-wide association studies of gastric cancer (GC) cases have revealed common gastric cancer susceptibility loci with low effect size. We investigated rare variants with high effect size via whole-exome sequencing (WES) of subjects with familial clustering of gastric cancer. WES of DNAs from the blood of 19 gastric cancer patients and 36 unaffected family members from 14 families with two or more gastric cancer patients were tested. Linkage analysis combined with association tests were performed using Pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) software. Based on the logarithm of odds (LOD) and permutation-based composite likelihood ratio test (CLRT) from pVAAST, MUC4 was identified as a predisposing gene (LOD P-value = 1.9×10-5; permutation-based P-value of CLRT ≤ 9.9×10-9). In a larger cohort consisting of 597 GC patients and 9,759 healthy controls genotyped with SNP array, we discovered common variants in MUC4 regions (rs148735556, rs11717039, and rs547775645) significantly associated with GC supporting the association of MUC4 with gastric cancer. And the MUC4 variants were found in higher frequency in The Cancer Genome Atlas Study (TCGA) germline samples of patients with multiple cancer types. Immunohistochemistry indicated that MUC4 was downregulated in the noncancerous gastric mucosa of subjects with MUC4 germline missense variants, suggesting that loss of the protective function of MUC4 predisposes an individual to gastric cancer. Rare variants in MUC4 can be novel gastric cancer susceptibility loci in Koreans possessing the familial clustering of gastric cancer.
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Affiliation(s)
- Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jung Hun Ohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
- * E-mail:
| | - Wonji Kim
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
| | - Kyungtaek Park
- Interdisciplinary Program of Bioinformatics, Seoul National University, Seoul, South Korea
| | - Sungho Won
- Interdisciplinary Program of Bioinformatics, Seoul National University, Seoul, South Korea
- Department of Public Health Sciences, Seoul National University, Seoul, South Korea
- Institute of Health and Environment, Seoul National University, Seoul, South Korea
| | - Lee Sael
- Department of Artificial Intelligence and Data Science, Ajou University, Seoul, South Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sun Min Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Sejoon Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hyun Joo An
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea
| | - Dong Man Jang
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Byung Woo Han
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Seung Joo Kang
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, South Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, South Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea
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Lyons K, Le LC, Pham YTH, Borron C, Park JY, Tran CTD, Tran TV, Tran HTT, Vu KT, Do CD, Pelucchi C, La Vecchia C, Zgibor J, Boffetta P, Luu HN. Gastric cancer: epidemiology, biology, and prevention: a mini review. Eur J Cancer Prev 2020; 28:397-412. [PMID: 31386635 DOI: 10.1097/cej.0000000000000480] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastric cancer is one of the most common causes of cancer-related mortality worldwide. The objective of this article is to review the epidemiology and biology of gastric cancer risk. This literature review explores the biological, clinical, and environmental factors that influence the rates of this disease and discuss the different intervention methods that may not only increase the awareness of gastric cancer but also increase screening in efforts to reduce the risk of gastric cancer. Helicobacter pylori infection is the primary risk factor for gastric cancer. Additional risk factors include geographical location, age, sex, smoking, socioeconomic status, dietary intake, and genetics. Primary and secondary prevention strategies such as dietary modifications and screenings are important measures for reducing the risk of gastric cancer. Interventions, such as H. pylori eradication through chemoprevention trials, have shown some potential as a preventative strategy. Although knowledge about gastric cancer risk has greatly increased, future research is warranted on the differentiation of gastric cancer epidemiology by subsite and exploring the interactions between H. pylori infection, genetics, and environmental factors. Better understanding of these relationships can help researchers determine the most effective intervention strategies for reducing the risk of this disease.
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Affiliation(s)
- Kiara Lyons
- Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida
| | - Linh C Le
- VinUniversity Project-Health Sciences.,Vinmec Healthcare System
| | | | - Claire Borron
- Icahn School of Medicine, Mount Sinai School of Medicine, Tisch Cancer Institute, New York City, New York
| | - Jong Y Park
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Chi T D Tran
- Vietnam Colorectal Cancer and Polyp Research Program, Vinmec Healthcare System
| | - Thuan V Tran
- Vietnam National Cancer Hospital.,Vietnam National Cancer Institute
| | - Huong T-T Tran
- Vietnam National Cancer Hospital.,Vietnam National Cancer Institute
| | - Khanh T Vu
- Department of Gastroenterology, Bach Mai Hospital
| | - Cuong D Do
- Department of Infectious Disease, Bach Mai Hospital, Hanoi, Vietnam
| | - Claudio Pelucchi
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Janice Zgibor
- Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida
| | - Paolo Boffetta
- Icahn School of Medicine, Mount Sinai School of Medicine, Tisch Cancer Institute, New York City, New York
| | - Hung N Luu
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health.,Division of Cancer Control and Population Sciences, Hillman Cancer Canter, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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