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Gholami M, Asouri M, Ahmadi AA. Genetic Variants and Haplotype Structures in the CASC Gene Family to Predict Cancer Risk: A Bioinformatics Study. Health Sci Rep 2024; 7:e70228. [PMID: 39640032 PMCID: PMC11618408 DOI: 10.1002/hsr2.70228] [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: 04/10/2024] [Revised: 10/01/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Background and Aims The cancer susceptibility (CASC) gene family of long noncoding RNAs (lncRNAs) plays an important role in cancer. The aim of this study was to identify genetic variants and haplotype structures of CASC genes associated with cancer risk. Methods Genome-wide association studies (GWAS) significant variants (p ≤ 5 × 10-8) on CASC family genes were identified from the GWAS Catalog-EMBL-EBI, and then cancer-associated variants on CASC genes were extracted. These variants were functionally analyzed, including lncRNA:miRNA binding sites, Regulomedb scores, and eQTL. The 1000 Genome Project genotyping data Phase III were used to identify haplotypic blocks. Finally, the genes associated with them were examined for expression and gene-gene correlation analyses using OncoDB. Results There were six haplotypic blocks in four genes. The GC, TA, and AGAC haplotypes are located in the CASC8 gene and increase the risk of prostate cancer, breast cancer, and colorectal cancer, respectively. The CA haplotype in the CASC15 gene increases the risk of neuroblastoma, AA haplotype in the CASC16 gene increases the risk of breast cancer, and ACGATG haplotype in the CASC17 gene increases the risk of prostate cancer (p ≤ 5 × 10-8). Their genes are interrelated and their expression is increased in these cancers. The rs2294214 is associated with skin cancer and has positive effects on five CASC15:miRNA binding sites. The rs3803662 is located in CASC16:miRNA binding sites, which has positive effects on hsa-miR-4475 and hsa-miR-7845-5p and negative effects on hsa-miR-4524a-3p and hsa-miR-4524b-3p. Conclusion These haplotypic structures and lncRNA:miRNA:SNP interactions on CASC family lncRNAs reveal novel genetic associations between CASC genes and various cancers.
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Affiliation(s)
- Morteza Gholami
- Department of ParamedicineAmol School of Paramedicine, Mazandaran University of Medical SciencesSariIran
- Metabolic Disorders Research CenterEndocrinology and Metabolism Molecular‐Cellular Sciences Institute, Tehran University of Medical SciencesTehranIran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran
| | - Mohsen Asouri
- Department of ParamedicineAmol School of Paramedicine, Mazandaran University of Medical SciencesSariIran
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Tian Y, Lin Y, Qu C, Arndt V, Baurley JW, Berndt SI, Bien SA, Bishop DT, Brenner H, Buchanan DD, Budiarto A, Campbell PT, Carreras-Torres R, Casey G, Chan AT, Chen R, Chen X, Conti DV, Díez-Obrero V, Dimou N, Drew DA, Figueiredo JC, Gallinger S, Giles GG, Gruber SB, Gunter MJ, Harlid S, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl KM, Joshi AD, Keku TO, Kawaguchi E, Kim AE, Kundaje A, Larsson SC, Marchand LL, Lewinger JP, Li L, Moreno V, Morrison J, Murphy N, Nan H, Nassir R, Newcomb PA, Obón-Santacana M, Ogino S, Ose J, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Potter JD, Prentice RL, Rennert G, Ruiz-Narvaez EA, Sakoda LC, Schoen RE, Shcherbina A, Stern MC, Su YR, Thibodeau SN, Thomas DC, Tsilidis KK, van Duijnhoven FJB, Van Guelpen B, Visvanathan K, White E, Wolk A, Woods MO, Wu AH, Peters U, Gauderman WJ, Hsu L, Chang-Claude J. Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk. Br J Cancer 2024; 130:1687-1696. [PMID: 38561434 PMCID: PMC11091089 DOI: 10.1038/s41416-024-02638-2] [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: 05/08/2023] [Revised: 02/20/2024] [Accepted: 02/22/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.
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Affiliation(s)
- Yu Tian
- School of Public Health, Capital Medical University, Beijing, China
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - James W Baurley
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- BioRealm LLC, Walnut, CA, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stephanie A Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - D Timothy Bishop
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - 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
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Arif Budiarto
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Peter T Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Robert Carreras-Torres
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute Dr Josep Trueta (IDIBGI), Salt, 17190, Girona, Spain
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Rui Chen
- School of Public Health, Capital Medical University, Beijing, China
| | - Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - David V Conti
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Virginia Díez-Obrero
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - David A Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
| | - Stephen B Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Marc J Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Akihisa Hidaka
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Kristina M Jordahl
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Amit D Joshi
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Eric Kawaguchi
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Andre E Kim
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, CA, USA
- Department of Computer Science, Stanford University, Stanford, CA, USA
| | - Susanna C Larsson
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | | | - Juan Pablo Lewinger
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Victor Moreno
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain
| | - John Morrison
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Hongmei Nan
- Department of Global Health, Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indianapolis, IN, USA
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Mireia Obón-Santacana
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Shuji Ogino
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Tokyo Medical and Dental University (Institute of Science Tokyo), Tokyo, Japan
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
- Hochschule Hannover, University of Applied Sciences and Arts, Department III: Media, Information and Design, Hannover, Germany
| | - Bens Pardamean
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Andrew J Pellatt
- Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anita R Peoples
- Huntsman Cancer Institute, Salt Lake City, UT, USA
- Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
- Research Centre for Hauora and Health, Massey University, Wellington, New Zealand
| | - Ross L Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Edward A Ruiz-Narvaez
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Anna Shcherbina
- Biomedical Informatics Program, Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Mariana C Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yu-Ru Su
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Duncan C Thomas
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | | | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Michael O Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL, Canada
| | - Anna H Wu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - W James Gauderman
- Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Department of Biostatistics, University of Washington, Seattle, WA, USA.
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- University Cancer Centre Hamburg (UCCH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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Kong L, Jin X. Dysregulation of deubiquitination in breast cancer. Gene 2024; 902:148175. [PMID: 38242375 DOI: 10.1016/j.gene.2024.148175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/04/2023] [Accepted: 01/16/2024] [Indexed: 01/21/2024]
Abstract
Breast cancer (BC) is a highly frequent malignant tumor that poses a serious threat to women's health and has different molecular subtypes, histological subtypes, and biological features, which act by activating oncogenic factors and suppressing cancer inhibitors. The ubiquitin-proteasome system (UPS) is the main process contributing to protein degradation, and deubiquitinases (DUBs) are reverse enzymes that counteract this process. There is growing evidence that dysregulation of DUBs is involved in the occurrence of BC. Herein, we review recent research findings in BC-associated DUBs, describe their nature, classification, and functions, and discuss the potential mechanisms of DUB-related dysregulation in BC. Furthermore, we present the successful treatment of malignant cancer with DUB inhibitors, as well as analyzing the status of targeting aberrant DUBs in BC.
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Affiliation(s)
- Lili Kong
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo 315211, Zhejiang, China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo 315211, Zhejiang, China.
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Zhang M, Wang X, Yang N, Zhu X, Lu Z, Cai Y, Li B, Zhu Y, Li X, Wei Y, Zhang S, Tian J, Miao X. Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks. SCIENCE CHINA. LIFE SCIENCES 2024; 67:132-148. [PMID: 37747674 DOI: 10.1007/s11427-023-2439-7] [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: 07/31/2023] [Accepted: 08/26/2023] [Indexed: 09/26/2023]
Abstract
Genome-wide association studies (GWASs) have identified over 140 colorectal cancer (CRC)-associated loci; however, target genes at the majority of loci and underlying molecular mechanisms are poorly understood. Here, we utilized a Bayesian approach, integrative risk gene selector (iRIGS), to prioritize risk genes at CRC GWAS loci by integrating multi-omics data. As a result, a total of 105 high-confidence risk genes (HRGs) were identified, which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC. Among the 105 HRGs, CEBPB, located at the 20q13.13 locus, acted as a transcription factor playing critical roles in cancer. Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK, PI3K-Akt, and Ras signaling. Next, by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls, we elucidated that rs1810503, a putative functional variant regulating CEBPB, was associated with CRC risk (OR=0.90, 95%CI=0.86-0.93, P=1.07×10-7). The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls. Mechanistically, the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via long-range promoter-enhancer interactions, mediated by the transcription factor, REST, and thus decreased CRC risk. In summary, our study provides a genetic resource and a generalizable strategy for CRC etiology investigation, and highlights the biological implications of CEBPB in CRC tumorigenesis, shedding new light on the etiology of CRC.
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Affiliation(s)
- Ming Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
- Research Center of Public Health, Renmin hospital of Wuhan University, Wuhan University, Wuhan, 430060, China
| | - Xiaoyang Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, Zhengzhou, 450008, China
| | - Nan Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
- Research Center of Public Health, Renmin hospital of Wuhan University, Wuhan University, Wuhan, 430060, China
| | - Xu Zhu
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zequn Lu
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yimin Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Bin Li
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Ying Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xiangpan Li
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yongchang Wei
- Department of Gastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430062, China
| | - Shaokai Zhang
- Department of Cancer Epidemiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, Zhengzhou, 450008, China.
| | - Jianbo Tian
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China.
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
- Research Center of Public Health, Renmin hospital of Wuhan University, Wuhan University, Wuhan, 430060, China.
| | - Xiaoping Miao
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan, 430071, China.
- Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
- Research Center of Public Health, Renmin hospital of Wuhan University, Wuhan University, Wuhan, 430060, China.
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430073, China.
- Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
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Mukamel RE, Handsaker RE, Sherman MA, Barton AR, Hujoel MLA, McCarroll SA, Loh PR. Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer. Cell 2023; 186:3659-3673.e23. [PMID: 37527660 PMCID: PMC10528368 DOI: 10.1016/j.cell.2023.07.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 04/07/2023] [Accepted: 07/03/2023] [Indexed: 08/03/2023]
Abstract
Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs genome-wide, we applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association and statistical fine-mapping analyses identified 58 VNTRs that appeared to influence a complex trait in UK Biobank, 18 of which also appeared to modulate expression or splicing of a nearby gene. Non-coding VNTRs at TMCO1 and EIF3H appeared to generate the largest known contributions of common human genetic variation to risk of glaucoma and colorectal cancer, respectively. Each of these two VNTRs associated with a >2-fold range of risk across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health and gene regulation.
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Affiliation(s)
- Ronen E Mukamel
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Robert E Handsaker
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
| | - Maxwell A Sherman
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Alison R Barton
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Bioinformatics and Integrative Genomics Program, Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Margaux L A Hujoel
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Steven A McCarroll
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
| | - Po-Ru Loh
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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6
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Aglago EK, Kim A, Lin Y, Qu C, Evangelou M, Ren Y, Morrison J, Albanes D, Arndt V, Barry EL, Baurley JW, Berndt SI, Bien SA, Bishop DT, Bouras E, Brenner H, Buchanan DD, Budiarto A, Carreras-Torres R, Casey G, Cenggoro TW, Chan AT, Chang-Claude J, Chen X, Conti DV, Devall M, Diez-Obrero V, Dimou N, Drew D, Figueiredo JC, Gallinger S, Giles GG, Gruber SB, Gsur A, Gunter MJ, Hampel H, Harlid S, Hidaka A, Harrison TA, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl K, Joshi AD, Kawaguchi ES, Keku TO, Kundaje A, Larsson SC, Marchand LL, Lewinger JP, Li L, Lynch BM, Mahesworo B, Mandic M, Obón-Santacana M, Moreno V, Murphy N, Nan H, Nassir R, Newcomb PA, Ogino S, Ose J, Pai RK, Palmer JR, Papadimitriou N, Pardamean B, Peoples AR, Platz EA, Potter JD, Prentice RL, Rennert G, Ruiz-Narvaez E, Sakoda LC, Scacheri PC, Schmit SL, Schoen RE, Shcherbina A, Slattery ML, Stern MC, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Tian Y, Ulrich CM, van Duijnhoven FJB, Van Guelpen B, Visvanathan K, Vodicka P, Wang J, White E, Wolk A, Woods MO, Wu AH, Zemlianskaia N, Hsu L, Gauderman WJ, Peters U, Tsilidis KK, Campbell PT. A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk. Cancer Res 2023; 83:2572-2583. [PMID: 37249599 PMCID: PMC10391330 DOI: 10.1158/0008-5472.can-22-3713] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/25/2023] [Accepted: 05/24/2023] [Indexed: 05/31/2023]
Abstract
Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. SIGNIFICANCE This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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Affiliation(s)
- Elom K. Aglago
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
| | - Andre Kim
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Marina Evangelou
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
| | - Yu Ren
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
| | - John Morrison
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elizabeth L. Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - James W. Baurley
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- BioRealm LLC, Walnut, California
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephanie A. Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - D. Timothy Bishop
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - 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
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Arif Budiarto
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
- Computer Science Department, School of Computer Science, Bina Nusantara University, Jakarta, Indonesia
| | - Robert Carreras-Torres
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain
| | - Graham Casey
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
| | - Tjeng Wawan Cenggoro
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Andrew T. Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - Xuechen Chen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - David V. Conti
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Matthew Devall
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia
| | - Virginia Diez-Obrero
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - David Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jane C. Figueiredo
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Graham G. Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Stephen B. Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte California
| | - Andrea Gsur
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Heather Hampel
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte California
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Akihisa Hidaka
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Tabitha A. Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Kristina Jordahl
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amit D. Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Eric S. Kawaguchi
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Temitope O. Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, California
- Department of Computer Science, Stanford University, Stanford, California
| | - Susanna C. Larsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Juan Pablo Lewinger
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia
| | - Brigid M. Lynch
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Bharuno Mahesworo
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Marko Mandic
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Mireia Obón-Santacana
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Victor Moreno
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Hongmei Nan
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indiana
- IU Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia
| | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Shuji Ogino
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Rish K. Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona
| | - Julie R. Palmer
- Department of Medicine, Boston University School of Medicine, Slone Epidemiology Center, Boston University, Boston, Massachusetts
| | - Nikos Papadimitriou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Bens Pardamean
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia
| | - Anita R. Peoples
- Huntsman Cancer Institute, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Elizabeth A. Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
- Research Centre for Hauora and Health, Massey University, Wellington, New Zealand
| | - Ross L. Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Edward Ruiz-Narvaez
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan
| | - Lori C. Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Peter C. Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio
| | | | - Robert E. Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Anna Shcherbina
- Department of Genetics, Stanford University, Stanford, California
- Department of Computer Science, Stanford University, Stanford, California
| | - Martha L. Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Mariana C. Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yu-Ru Su
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Catherine M. Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stephen N. Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Duncan C. Thomas
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yu Tian
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- School of Public Health, Capital Medical University, Beijing, China
| | - Cornelia M. Ulrich
- Huntsman Cancer Institute, Salt Lake City, Utah
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Franzel JB van Duijnhoven
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jun Wang
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael O. Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada
| | - Anna H. Wu
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Natalia Zemlianskaia
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Biostatistics, University of Washington, Seattle, Washington
| | - W. James Gauderman
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Konstantinos K. Tsilidis
- Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Peter T. Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
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7
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Abbes S, Baldi S, Sellami H, Amedei A, Keskes L. Molecular methods for colorectal cancer screening: Progress with next-generation sequencing evolution. World J Gastrointest Oncol 2023; 15:425-442. [PMID: 37009313 PMCID: PMC10052664 DOI: 10.4251/wjgo.v15.i3.425] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/02/2023] [Accepted: 02/14/2023] [Indexed: 03/14/2023] Open
Abstract
Currently, colorectal cancer (CRC) represents the third most common malignancy and the second most deadly cancer worldwide, with a higher incidence in developed countries. Like other solid tumors, CRC is a heterogeneous genomic disease in which various alterations, such as point mutations, genomic rearrangements, gene fusions or chromosomal copy number alterations, can contribute to the disease development. However, because of its orderly natural history, easily accessible onset location and high lifetime incidence, CRC is ideally suited for preventive intervention, but the many screening efforts of the last decades have been compromised by performance limitations and low penetrance of the standard screening tools. The advent of next-generation sequencing (NGS) has both facilitated the identification of previously unrecognized CRC features such as its relationship with gut microbial pathogens and revolutionized the speed and throughput of cataloguing CRC-related genomic alterations. Hence, in this review, we summarized the several diagnostic tools used for CRC screening in the past and the present, focusing on recent NGS approaches and their revolutionary role in the identification of novel genomic CRC characteristics, the advancement of understanding the CRC carcinogenesis and the screening of clinically actionable targets for personalized medicine.
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Affiliation(s)
- Salma Abbes
- Laboratory of Parasitic and Fungal Molecular Biology, University of Sfax, Sfax 3029, Tunisia
| | - Simone Baldi
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Hayet Sellami
- Drosophila Research Unit-Parasitology and Mycologie Laboratory, University of Sfax, Sfax 3029, Tunisia
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Careggi University Hospital, Florence 50134, Italy
| | - Leila Keskes
- Laboratory of Human Molecular Genetic, University of Sfax, Sfax 3029, Tunisia
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8
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Wei Y, Chen W, Li Z, Xie K, Liu F. EIF3H stabilizes CCND1 to promotes intrahepatic cholangiocarcinoma progression via Wnt/β-catenin signaling. FASEB J 2022; 36:e22647. [PMID: 36350008 DOI: 10.1096/fj.202200913r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/06/2022] [Accepted: 10/31/2022] [Indexed: 11/11/2022]
Abstract
Cholangiocarcinoma (CCA) is a group of tumors that arise along the human biliary duct tree, ranking second in primary hepatic malignancies. Intrahepatic CCA (iCCA) represents about 10%-20% of CCAs. There is an increasing body of evidence suggesting that iCCAs' incidence and mortality have been increasing globally over the past few decades. In this study, we found that the EIF3H expression level in iCCA tissues was significantly increased compared to the adjacent non-cancerous tissues by immunohistochemistry analysis (IHC). A similar tendency of EIF3H mRNA and protein level was confirmed in iCCA cell lines using RT-qPCR and Western blot. EIF3H has been identified as a critical molecule that plays a pro-neoplasmic role in iCCA both in vivo and in vitro, such as proliferation, migration, and anti-apoptosis. Mechanistically, we found that EIF3H knockdown can promote the degradation of CCND1 and the proteolysis of CCND1 is mediated by ubiquitin-proteasome system (UPS). Thus, we come to the conclusion that EIF3H promotes proliferation and migration of iCCAs, inhibiting apoptosis of iCCA cells at the same time by stabilizing the CCND1 protein structure. Our findings provide insights into the mechanism of tumorigenesis role of EIF3H in iCCAs and a potential therapeutic target for iCCA treatment.
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Affiliation(s)
- Yajun Wei
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
| | - Wei Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
| | - Zihan Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
| | - Kun Xie
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
| | - Fubao Liu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
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Archambault AN, Jeon J, Lin Y, Thomas M, Harrison TA, Bishop DT, Brenner H, Casey G, Chan AT, Chang-Claude J, Figueiredo JC, Gallinger S, Gruber SB, Gunter MJ, Guo F, Hoffmeister M, Jenkins MA, Keku TO, Le Marchand L, Li L, Moreno V, Newcomb PA, Pai R, Parfrey PS, Rennert G, Sakoda LC, Lee JK, Slattery ML, Song M, Win AK, Woods MO, Murphy N, Campbell PT, Su YR, Lansdorp-Vogelaar I, Peterse EFP, Cao Y, Zeleniuch-Jacquotte A, Liang PS, Du M, Corley DA, Hsu L, Peters U, Hayes RB. Risk Stratification for Early-Onset Colorectal Cancer Using a Combination of Genetic and Environmental Risk Scores: An International Multi-Center Study. J Natl Cancer Inst 2022; 114:528-539. [PMID: 35026030 PMCID: PMC9002285 DOI: 10.1093/jnci/djac003] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/04/2021] [Accepted: 01/06/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants. METHODS Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve. RESULTS Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores. CONCLUSIONS Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.
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Affiliation(s)
- Alexi N Archambault
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA
| | - Jihyoun Jeon
- Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Minta Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - D Timothy Bishop
- Leeds Institute of Medical Research, St. James’s University of Leeds, Leeds, UK
| | - 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
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Stephen B Gruber
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Feng Guo
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Rish Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | | | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Jeffrey K Lee
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Michael O Woods
- Discipline of Genetics, Memorial University of Newfoundland, St John’s, NL, Canada
| | - Neil Murphy
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Peter T Campbell
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Yu-Ru Su
- Biostatistics Unit, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Iris Lansdorp-Vogelaar
- Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Elisabeth F P Peterse
- Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
- Washington University School of Medicine, Alvin J. Siteman Cancer Center, St Louis, MO, USA
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Anne Zeleniuch-Jacquotte
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA
| | - Peter S Liang
- Department of Medicine, New York University School of Medicine, New York, NY, USA
| | - Mengmeng Du
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Richard B Hayes
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA
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10
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Lim EB, Oh HS, Kim KC, Kim MH, Kim YJ, Kim BJ, Nho CW, Cho YS. Identification and functional validation of HLA-C as a potential gene involved in colorectal cancer in the Korean population. BMC Genomics 2022; 23:261. [PMID: 35379174 PMCID: PMC8981957 DOI: 10.1186/s12864-022-08509-5] [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: 07/13/2021] [Accepted: 03/25/2022] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common cancer worldwide and is influenced by environmental and genetic factors. Although numerous genetic loci for CRC have been identified, the overall understanding of the genetic factors is yet to be elucidated. We sought to discover new genes involved in CRC applying genetic association analysis and functional study. RESULTS We conducted exome array analysis on 194 CRC and 600 control subjects for discovering new candidate CRC genes. Fisher's exact test detected one exome-wide significant functional locus for CRC on SMCO1 (P < 10-6) and two suggestive functional loci on HLA-C and NUTM1 (10-6 ≤ P < 10-4). To evaluate the biological role of three candidate CRC genes, the differential expression of these genes between CRC and non-cancer colorectal cells was analyzed using qRT-PCR and publicly available gene expression data. Of three genes, HLA-C consistently revealed the significant down-regulation in CRC cells. In addition, we detected a reduction in cell viability in the HLA-C overexpression CRC cell line, implying the functional relevance of HLA-C in CRC. To understand the underlying mechanism exerted by HLA-C in CRC development, we conducted RNA sequencing analyses of HLA-C overexpression CRC cells and non-cancer colorectal cells. Pathway analysis detected that significantly down-regulated genes in HLA-C overexpression CRC cells were highly enriched in cancer-related signaling pathways such as JAK/STAT, ErbB, and Hedgehog signaling pathways. CONCLUSIONS Exome array CRC case-control analysis followed by functional validation demonstrated that HLA-C likely exerts its influence on CRC development via cancer-related signaling pathways.
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Affiliation(s)
- Eun Bi Lim
- Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Ho-Suk Oh
- Department of Internal Medicine, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon-do, Republic of Korea
| | - Kang Chang Kim
- Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Moon-Ho Kim
- Department of Internal Medicine, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon-do, Republic of Korea
| | - Young Jin Kim
- Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, Republic of Korea
| | - Bong Jo Kim
- Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, Republic of Korea
| | - Chu Won Nho
- Convergence Research Center for Smart Farm Solution, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea
| | - Yoon Shin Cho
- Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea.
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11
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Huang X, Yang Z, Zhang J, Wang R, Fan J, Zhang H, Xu R, Li X, Yu S, Long L, Huang H. A Bibliometric Analysis Based on Web of Science: Current Perspectives and Potential Trends of SMAD7 in Oncology. Front Cell Dev Biol 2022; 9:712732. [PMID: 35252215 PMCID: PMC8894759 DOI: 10.3389/fcell.2021.712732] [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: 05/24/2021] [Accepted: 12/31/2021] [Indexed: 12/11/2022] Open
Abstract
Background: The number of publications on SMAD7 in the field of oncology is increasing rapidly with an upward tendency. In most cases, the mechanisms of carcinogenesis usually relate to disorders of signaling activity. Considering the crucial role of SMAD7 in the crosstalk of multiple signaling pathways, it is necessary to clarify and define the dominant research topics, core authors, and their cumulative research contributions, as well as the cooperative relationships among documents or researchers. Methods: Altogether, 3477 documents were retrieved from the Web of Science Core Collection with the following criteria: TS= (SMAD7 OR SMAD7-protein OR Small-Mothers-Against-Decapentaplegic-7) refined by WEB OF SCIENCE CATEGORY (ONCOLOGY) AND [excluding] PUBLICATION YEARS (2021) AND DOCUMENT TYPES (ARTICLE OR REVIEW) AND LANGUAGES (ENGLISH) AND WEB OF SCIENCE INDEX (Web of Science Core Collection, SCI), and the timespan of 2011–2020. Bibliometric visualization analysis was conducted with CiteSpace and VOSviewer. Results: The number of documents grew each year. A total of 2703 articles and 774 reviews were identified from 86 countries/regions, 3524 organizations, 928 journals, and 19,745 authors. China was the most prolific country, with 1881 documents. Contributions from China, the United States, and Germany were the most substantial. The most influential author was Lan Huiyao at The Chinese University of Hong Kong, with 24 publications and 2348 total citations. The bibliometric analysis showed that multilateral cooperation among diverse institutions or investigators was beneficial to high-quality outputs. The keyword “PPAR-gamma” exhibited the strongest burst in recent years, suggesting a potent research focus in the future. Conclusion: Research on SMAD7 in oncology is continuously developing. Bibliometrics is an interesting tool to present the characteristics of publication years, main authors, and productive organizations in a visualized way. It is worth mentioning that a prospective focus might be the specific mechanism of the interaction of PPAR-gamma with SMAD7 in oncology. In all, bibliometric analysis provides an overview and identifies potential research trends for further studies in this academic field.
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Affiliation(s)
- Xueying Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhiying Yang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
- Changsha Health Vocational College, Changsha, China
| | - Jinning Zhang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruojiao Wang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Jiahui Fan
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Heng Zhang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Rong Xu
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Xia Li
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
- Department of Histology and Embryology, School of Basic Medical Science, Xinjiang Medical University, Urumqi, China
| | - Siying Yu
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - Linna Long
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, China
- *Correspondence: He Huang,
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12
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Abdi E, Latifi-Navid S, Latifi-Navid H. Long noncoding RNA polymorphisms and colorectal cancer risk: Progression and future perspectives. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2022; 63:98-112. [PMID: 35275417 DOI: 10.1002/em.22477] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 02/25/2022] [Accepted: 03/08/2022] [Indexed: 06/14/2023]
Abstract
Colorectal cancer (CRC) is one of the most common cancers causing death worldwide. Many long noncoding RNAs (lncRNAs) have possible carcinogenic or tumor suppressor functions. Some lncRNA polymorphisms are useful for predicting cancer risk, and may help advance personalized therapy management. While the use of lncRNAs as biomarkers is promising, there are still drawbacks, and further studies are needed to verify the consistency of current outcomes in large-scale populations and different ethnicities. Single nucleotide polymorphisms (SNPs) can disrupt a lncRNAs' function, thus enhancing or hindering disease occurrence. SNPs can directly influence the lncRNA expression by interfering with transcription factor binding or affecting indirectly a regulatory factors' expression. Moreover, the association between lncRNAs and other RNAs or proteins may be disrupted by SNPs. This research sought to assess the association between lncRNA polymorphisms and CRC risk, as well as clinical and therapeutic consequences in certain cases.
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Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Hamid Latifi-Navid
- Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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13
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Niedermaier T, Balavarca Y, Gies A, Weigl K, Guo F, Alwers E, Hoffmeister M, Brenner H. Variation of Positive Predictive Values of Fecal Immunochemical Tests by Polygenic Risk Score in a Large Screening Cohort. Clin Transl Gastroenterol 2022; 13:e00458. [PMID: 35060941 PMCID: PMC8963839 DOI: 10.14309/ctg.0000000000000458] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Prevalence of colorectal neoplasms varies by polygenic risk scores (PRS). We aimed to assess to what extent a PRS might be relevant for defining personalized cutoff values for fecal immunochemical tests (FITs) in colorectal cancer screening. METHODS Among 5,306 participants of screening colonoscopy who provided a stool sample for a quantitative FIT (Ridascreen Hemoglobin or FOB Gold) before colonoscopy, a PRS was determined, based on the number of risk alleles in 140 single nucleotide polymorphisms. Subjects were classified into low, medium, and high genetic risk of colorectal neoplasms according to PRS tertiles. We calculated positive predictive values (PPVs) and numbers needed to scope (NNS) to detect 1 advanced neoplasm (AN) by the risk group, and cutoff variation needed to achieve comparable PPVs across risk groups in the samples tested with Ridascreen (N = 1,271) and FOB Gold (N = 4,035) independently, using cutoffs yielding 85%, 90%, or 95% specificity. RESULTS Performance of both FITs was very similar within each PRS group. For a given cutoff, PPVs were consistently higher by 11%-15% units in the high-risk PRS group compared with the low-risk group (all P values < 0.05). Correspondingly, NNS to detect 1 advanced neoplasm varied from 2 (high PRS, high cutoff) to 5 (low PRS, low cutoff). Conversely, very different FIT cutoffs would be needed to ensure comparable PPVs across PRS groups. DISCUSSION PPVs and NNS of FITs varied widely across people with high and low genetic risk score. Further research should evaluate the relevance of these differences for personalized colorectal cancer screening.
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Affiliation(s)
- Tobias Niedermaier
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;
| | - Yesilda Balavarca
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany;
| | - Anton Gies
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany;
| | - Korbinian Weigl
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;
| | - Feng Guo
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;
| | - Elizabeth Alwers
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;
| | - 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
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14
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Liu W, Mahdessian H, Helgadottir H, Zhou X, Thutkawkorapin J, Jiao X, Wolk A, Lindblom A. Colorectal cancer risk susceptibility loci in a Swedish population. Mol Carcinog 2021; 61:288-300. [PMID: 34758156 DOI: 10.1002/mc.23366] [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: 04/05/2021] [Revised: 10/20/2021] [Accepted: 10/20/2021] [Indexed: 11/12/2022]
Abstract
To search for colorectal cancer (CRC) risk loci, Swedish samples were used for a genome-wide haplotype analysis. A logistic regression model was employed in 2663 CRC cases and 1642 controls in the discovery analysis. Three analyses were done, on all, familial-, and nonfamilial CRC samples and only results with odds ratio (OR) > 1 were analyzed. single nucleotide polymorphism (SNP) analysis did not generate any statistically significant results. Haplotype analysis suggested novel loci, on chromosome 2q36.1 (OR = 1.71, p value = 5.6924 × 10-8 ) in all CRC samples, chromosome 1q43 (OR = 4.04 p value = 3.24 × 10-8 ) in familial CRC samples, and two hits in nonfamilial CRC samples, chromosomes 2q36.1 (OR = 1.71 p value = 5.69 × 10-8 ) and 3p24.3 (OR = 1.62 p value = 6.21 × 10-9 ). Moreover, one locus on chromosome 20q13.33 was suggested in analyses of all samples, and five more novel loci were suggested on chromosomes 10q25.3, 15q,22.31, 17p11.2, 1p34.2, and 3q24. The haplotypes from the analysis of all samples were replicated in a second study of CRC cases and controls from the same part of Sweden. In summary, using haplotype analysis in Swedish CRC samples, the best hits were novel loci and the locus on chromosomes 2q36.1 and 20q13.33 suggested in the analysis of all samples were confirmed in a second cohort. The ORs were often higher than ORs from published genome-wide association study (GWAS). The study suggested it was possible that a risk locus could involve more than one gene, and that haplotypes could give information on the gene or genes possibly involved in the risk at specific locus.
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Affiliation(s)
- Wen Liu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Hovsep Mahdessian
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Hafdis Helgadottir
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Xingwu Zhou
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Xiang Jiao
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | | | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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15
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Forgacova N, Gazdarica J, Budis J, Radvanszky J, Szemes T. Repurposing non-invasive prenatal testing data: Population study of single nucleotide variants associated with colorectal cancer and Lynch syndrome. Oncol Lett 2021; 22:779. [PMID: 34594420 PMCID: PMC8456492 DOI: 10.3892/ol.2021.13040] [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: 04/29/2021] [Accepted: 07/16/2021] [Indexed: 12/24/2022] Open
Abstract
In our previous work, genomic data generated through non-invasive prenatal testing (NIPT) based on low-coverage massively parallel whole-genome sequencing of total plasma DNA of pregnant women in Slovakia was described as a valuable source of population specific data. In the present study, these data were used to determine the population allele frequency of common risk variants located in genes associated with colorectal cancer (CRC) and Lynch syndrome (LS). Allele frequencies of identified variants were compared with six world populations to detect significant differences between populations. Finally, variants were interpreted, functional consequences were searched for and clinical significance of variants was investigated using publicly available databases. Although the present study did not identify any pathogenic variants associated with CRC or LS in the Slovak population using NIPT data, significant differences were observed in the allelic frequency of risk CRC variants previously reported in genome-wide association studies and common variants located in genes associated with LS. As Slovakia is one of the leading countries with the highest incidence of CRC among male patients in the world, there is a need for studies dedicated to investigating the cause of such a high incidence of CRC in Slovakia. The present study also assumed that extensive cross-country data aggregation of NIPT results would represent an unprecedented source of information concerning human genome variation in cancer research.
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Affiliation(s)
- Natalia Forgacova
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia.,Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 841 04 Bratislava, Slovakia
| | - Juraj Gazdarica
- Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 841 04 Bratislava, Slovakia.,Geneton Ltd., 841 04 Bratislava, Slovakia.,Science Support Section, Slovak Centre of Scientific and Technical Information, 811 04 Bratislava, Slovakia
| | - Jaroslav Budis
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia.,Geneton Ltd., 841 04 Bratislava, Slovakia.,Science Support Section, Slovak Centre of Scientific and Technical Information, 811 04 Bratislava, Slovakia
| | - Jan Radvanszky
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia.,Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 841 04 Bratislava, Slovakia.,Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | - Tomas Szemes
- Comenius University Science Park, Comenius University, 841 04 Bratislava, Slovakia.,Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, 841 04 Bratislava, Slovakia.,Geneton Ltd., 841 04 Bratislava, Slovakia
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16
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Mur P, Bonifaci N, Díez-Villanueva A, Munté E, Alonso MH, Obón-Santacana M, Aiza G, Navarro M, Piñol V, Brunet J, Tomlinson I, Capellá G, Moreno V, Valle L. Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants. Cancers (Basel) 2021; 13:3857. [PMID: 34359758 PMCID: PMC8345397 DOI: 10.3390/cancers13153857] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/20/2021] [Accepted: 07/26/2021] [Indexed: 01/07/2023] Open
Abstract
A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.
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Affiliation(s)
- Pilar Mur
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Nuria Bonifaci
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
| | - Anna Díez-Villanueva
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology, IDIBELL, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | - Elisabet Munté
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
| | - Maria Henar Alonso
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology, IDIBELL, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | - Mireia Obón-Santacana
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology, IDIBELL, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
| | - Gemma Aiza
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
| | - Matilde Navarro
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Virginia Piñol
- Gastroenterology Unit, Hospital Universitario de Girona Dr Josep Trueta, 17007 Girona, Spain;
- School of Medicine, University of Girona, 17071 Girona, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- School of Medicine, University of Girona, 17071 Girona, Spain
- Catalan Institute of Oncology, IDIBGi, 17007 Girona, Spain
| | - Ian Tomlinson
- Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK;
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Victor Moreno
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology, IDIBELL, 08908 Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, 08907 Barcelona, Spain
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, 08908 Barcelona, Spain; (P.M.); (N.B.); (E.M.); (G.A.); (M.N.); (J.B.); (G.C.)
- Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; (A.D.-V.); (M.H.A.); (M.O.-S.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
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17
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Zhang T, Liu N, Wei W, Zhang Z, Li H. Integrated Analysis of Weighted Gene Coexpression Network Analysis Identifying Six Genes as Novel Biomarkers for Alzheimer's Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9918498. [PMID: 34367470 PMCID: PMC8339876 DOI: 10.1155/2021/9918498] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 07/14/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease; however, there are no comprehensive therapeutic interventions. Therefore, this study is aimed at identifying novel molecular targets that may improve the diagnosis and treatment of patients with AD. METHODS In our study, GSE5281 microarray dataset from the GEO database was collected and screened for differential expression analysis. Genes with a P value of <0.05 and ∣log2FoldChange | >0.5 were considered differentially expressed genes (DEGs). We further profiled and identified AD-related coexpression genes using weighted gene coexpression network analysis (WGCNA). Functional enrichment analysis was performed to determine the characteristics and pathways of the key modules. We constructed an AD-related model based on hub genes by logistic regression and least absolute shrinkage and selection operator (LASSO) analyses, which was also verified by the receiver operating characteristic (ROC) curve. RESULTS In total, 4674 DEGs were identified. Nine distinct coexpression modules were identified via WGCNA; among these modules, the blue module showed the highest positive correlation with AD (r = 0.64, P = 3e - 20), and it was visualized by establishing a protein-protein interaction network. Moreover, this module was particularly enriched in "pathways of neurodegeneration-multiple diseases," "Alzheimer disease," "oxidative phosphorylation," and "proteasome." Sixteen genes were identified as hub genes and further submitted to a LASSO regression model, and six genes (EIF3H, RAD51C, FAM162A, BLVRA, ATP6V1H, and BRAF) were identified based on the model index. Additionally, we assessed the accuracy of the LASSO model by plotting an ROC curve (AUC = 0.940). CONCLUSIONS Using the WGCNA and LASSO models, our findings provide a better understanding of the role of biomarkers EIF3H, RAD51C, FAM162A, BLVRA, ATP6V1H, and BRAF and provide a basis for further studies on AD progression.
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Affiliation(s)
- Tingting Zhang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Nanyang Liu
- Department of Geratology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, China
| | - Wei Wei
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Zhen Zhang
- Department of Geratology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, China
| | - Hao Li
- Department of Geratology, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing, China
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18
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Dorman A, Binenbaum I, Abu-Toamih Atamni HJ, Chatziioannou A, Tomlinson I, Mott R, Iraqi FA. Genetic mapping of novel modifiers for Apc Min induced intestinal polyps' development using the genetic architecture power of the collaborative cross mice. BMC Genomics 2021; 22:566. [PMID: 34294033 PMCID: PMC8299641 DOI: 10.1186/s12864-021-07890-x] [Citation(s) in RCA: 7] [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: 11/12/2020] [Accepted: 07/14/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated ApcMin/+ (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with ApcMin/+, we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-ApcMin/+mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-ApcMin/+ males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1-3) of small intestinal and colon were recorded. RESULTS The number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63-17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the ApcMin/+ mutation. CONCLUSIONS Genomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements - and possible epistatic effects - located in the mapped QTL.
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Affiliation(s)
- Alexandra Dorman
- Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, Ramat Aviv, 69978 Tel-Aviv, Israel
| | - Ilona Binenbaum
- Department of Biology, University of Patras, Patras, Greece
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Hanifa J. Abu-Toamih Atamni
- Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, Ramat Aviv, 69978 Tel-Aviv, Israel
| | | | - Ian Tomlinson
- Cancer Research UK Edinburgh Centre, Charles and Ethel Barr Chair of Cancer Research, University of Edinburgh, Edinburgh, UK
| | - Richard Mott
- Department of Genetics, University Collage of London, London, UK
| | - Fuad A. Iraqi
- Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, Ramat Aviv, 69978 Tel-Aviv, Israel
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19
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Huyghe JR, Harrison TA, Bien SA, Hampel H, Figueiredo JC, Schmit SL, Conti DV, Chen S, Qu C, Lin Y, Barfield R, Baron JA, Cross AJ, Diergaarde B, Duggan D, Harlid S, Imaz L, Kang HM, Levine DM, Perduca V, Perez-Cornago A, Sakoda LC, Schumacher FR, Slattery ML, Toland AE, van Duijnhoven FJB, Van Guelpen B, Agudo A, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Banbury BL, Bassik MC, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Boutron-Ruault MC, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Caan BJ, Campbell PT, Carr PR, Castells A, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Curtis KR, de la Chapelle A, Easton DF, English DR, Feskens EJM, Gala M, Gallinger SJ, Gauderman WJ, Giles GG, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hoffmeister M, Hopper JL, Hsu WL, Huang WY, Hudson TJ, Jenab M, Jenkins MA, Joshi AD, Keku TO, Kooperberg C, Kühn T, Küry S, Le Marchand L, Lejbkowicz F, Li CI, Li L, Lieb W, Lindblom A, Lindor NM, Männistö S, Markowitz SD, Milne RL, Moreno L, Murphy N, Nassir R, Offit K, Ogino S, Panico S, Parfrey PS, Pearlman R, Pharoah PDP, Phipps AI, Platz EA, Potter JD, Prentice RL, Qi L, Raskin L, Rennert G, Rennert HS, Riboli E, Schafmayer C, Schoen RE, Seminara D, Song M, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Trichopoulou A, Ulrich CM, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl K, Weinstein SJ, White E, Wolk A, Woods MO, Wu AH, Abecasis GR, Nickerson DA, Scacheri PC, Kundaje A, Casey G, Gruber SB, Hsu L, Moreno V, Hayes RB, Newcomb PA, Peters U. Genetic architectures of proximal and distal colorectal cancer are partly distinct. Gut 2021; 70:1325-1334. [PMID: 33632709 PMCID: PMC8223655 DOI: 10.1136/gutjnl-2020-321534] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 11/26/2020] [Accepted: 12/18/2020] [Indexed: 01/14/2023]
Abstract
OBJECTIVE An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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Affiliation(s)
- Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Stephanie A Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Jane C Figueiredo
- Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | - David V Conti
- Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Sai Chen
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Richard Barfield
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - John A Baron
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, Imperial College London, London, UK
| | - Brenda Diergaarde
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - David Duggan
- Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, Arizona, USA
| | - Sophia Harlid
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Liher Imaz
- Public Health Division of Gipuzkoa, Health Department of Basque Country, San Sebastian, Spain
| | - Hyun Min Kang
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - David M Levine
- Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - Vittorio Perduca
- Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France
- Centre for Research in Epidemiology and Population Health (CESP), Institut pour la Santé et la Recherche Médicale (INSERM) U1018, Université Paris-Saclay, Villejuif, France
| | - Aurora Perez-Cornago
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
| | - Fredrick R Schumacher
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah, USA
| | - Amanda E Toland
- Departments of Cancer Biology and Genetics and Internal Medicine, The Ohio State University, Columbus, Ohio, USA
| | | | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Antonio Agudo
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - M Henar Alonso
- Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Kristin Anderson
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Coral Arnau-Collell
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Michael C Bassik
- Department of Genetics, Stanford University, Stanford, California, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Stéphane Bézieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | - D Timothy Bishop
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Juergen Boehm
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah Health, Salt Lake City, Utah, USA
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany
| | - Marie-Christine Boutron-Ruault
- Centre for Research in Epidemiology and Population Health (CESP), Institut pour la Santé et la Recherche Médicale (INSERM) U1018, Université Paris-Saclay, Villejuif, France
- Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Centre (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefanie Brezina
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Stephan Buch
- Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Daniel D Buchanan
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | | | - Bette J Caan
- Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA
| | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA
| | - Prudence R Carr
- Division of Clinical Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Antoni Castells
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Keith R Curtis
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Albert de la Chapelle
- Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Douglas F Easton
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Dallas R English
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Edith J M Feskens
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Manish Gala
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Steven J Gallinger
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - W James Gauderman
- Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Phyllis J Goodman
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - John S Grove
- University of Hawai'i Cancer Center, Honolulu, Hawaii, USA
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Robert W Haile
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jochen Hampe
- Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea
| | - Wan-Ling Hsu
- Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Thomas J Hudson
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Mazda Jenab
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Amit D Joshi
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Charles Kooperberg
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Sébastien Küry
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | | | - Flavio Lejbkowicz
- The Clalit Health Services, Personalized Genomic Service, Carmel Medical Center, Haifa, Israel
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
| | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Wolfgang Lieb
- Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Noralane M Lindor
- Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona, USA
| | - Satu Männistö
- Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland
| | - Sanford D Markowitz
- Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA
| | - Roger L Milne
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Lorena Moreno
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Neil Murphy
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Rami Nassir
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Shuji Ogino
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Salvatore Panico
- Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Naples, Italy
| | - Patrick S Parfrey
- Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Rachel Pearlman
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Paul D P Pharoah
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Ross L Prentice
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Lihong Qi
- Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California, USA
| | - Leon Raskin
- Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Hedy S Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel
- Clalit National Cancer Control Center, Haifa, Israel
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Elio Riboli
- School of Public Health, Imperial College London, London, UK
| | - Clemens Schafmayer
- Department of General Surgery, University Hospital Rostock, Rostock, Germany
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Daniela Seminara
- Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Yu-Ru Su
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Catherine M Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, Minnesota, USA
| | - Duncan C Thomas
- Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah Health, Salt Lake City, Utah, USA
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Korbinian Weigl
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Stephanie J Weinstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Michael O Woods
- Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Anna H Wu
- Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Goncalo R Abecasis
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA
| | - Deborah A Nickerson
- Department of Genome Sciences, University of Washington, Seattle, Washington, USA
| | - Peter C Scacheri
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Anshul Kundaje
- Department of Genetics, Stanford University, Stanford, California, USA
- Department of Computer Science, Stanford University, Stanford, California, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Stephen B Gruber
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA
- City of Hope National Medical Center, Duarte, California, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Biostatistics, University of Washington, Seattle, Washington, USA
| | - Victor Moreno
- Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Richard B Hayes
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
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20
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Genetic risk factors for colorectal cancer in multiethnic Indonesians. Sci Rep 2021; 11:9988. [PMID: 33976257 PMCID: PMC8113452 DOI: 10.1038/s41598-021-88805-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 04/14/2021] [Indexed: 11/09/2022] Open
Abstract
Colorectal cancer is a common cancer in Indonesia, yet it has been understudied in this resource-constrained setting. We conducted a genome-wide association study focused on evaluation and preliminary discovery of colorectal cancer risk factors in Indonesians. We administered detailed questionnaires and collecting blood samples from 162 colorectal cancer cases throughout Makassar, Indonesia. We also established a control set of 193 healthy individuals frequency matched by age, sex, and ethnicity. A genome-wide association analysis was performed on 84 cases and 89 controls passing quality control. We evaluated known colorectal cancer genetic variants using logistic regression and established a genome-wide polygenic risk model using a Bayesian variable selection technique. We replicate associations for rs9497673, rs6936461 and rs7758229 on chromosome 6; rs11255841 on chromosome 10; and rs4779584, rs11632715, and rs73376930 on chromosome 15. Polygenic modeling identified 10 SNP associated with colorectal cancer risk. This work helps characterize the relationship between variants in the SCL22A3, SCG5, GREM1, and STXBP5-AS1 genes and colorectal cancer in a diverse Indonesian population. With further biobanking and international research collaborations, variants specific to colorectal cancer risk in Indonesians will be identified.
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21
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Erben V, Carr PR, Guo F, Weigl K, Hoffmeister M, Brenner H. Individual and Joint Associations of Genetic Risk and Healthy Lifestyle Score with Colorectal Neoplasms Among Participants of Screening Colonoscopy. Cancer Prev Res (Phila) 2021; 14:649-658. [PMID: 33653736 DOI: 10.1158/1940-6207.capr-20-0576] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/21/2021] [Accepted: 02/27/2021] [Indexed: 12/24/2022]
Abstract
Genetic and lifestyle factors contribute to colorectal cancer risk. We investigated their individual and joint associations with various stages of colorectal carcinogenesis. We assessed associations of a polygenic risk score (PRS) and a healthy lifestyle score (HLS) with presence of nonadvanced adenomas and advanced neoplasms among 2,585 participants of screening colonoscopy from Germany. The PRS and HLS individually showed only weak associations with presence of nonadvanced adenomas; stronger associations were observed with advanced neoplasms (ORs, 95% CI, for highest vs. lowest risk tertile: PRS 2.27, 1.78-2.88; HLS 1.96, 1.53-2.51). The PRS was associated with higher odds of advanced neoplasms among carriers of any neoplasms (1.65, 1.23-2.22). Subjects in the highest risk tertile (vs. lowest tertile) of both scores had higher risks for nonadvanced adenomas (1.77, 1.09-2.86), for advanced neoplasms (3.95, 2.53-6.16) and, among carriers of any neoplasms, for advanced versus nonadvanced neoplasms (2.26, 1.31-3.92). Both scores were individually associated with increased risk of nonadvanced adenomas and, much more pronounced, advanced neoplasms. The similarly strong association in relative terms across all levels of genetic risk implies that a healthy lifestyle may be particularly beneficial in those at highest genetic risk, given that the same relative risk reduction in this group would imply a stronger absolute risk reduction. Genetic factors may be of particular relevance for the transition of nonadvanced to advanced adenomas. PREVENTION RELEVANCE: Genetic factors have strong impact on the risk of colorectal neoplasms, which may be reduced by healthy lifestyle. Similarly strong associations in relative terms across all levels of genetic risk imply that a healthy lifestyle may be beneficial due to higher absolute risk reduction in those at highest genetic risk.
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Affiliation(s)
- Vanessa Erben
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Prudence R Carr
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Feng Guo
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Korbinian Weigl
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
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22
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Wang H, Gu D, Yu M, Hu Y, Chen Z, Huo X, Yu T, Chen J, Zheng Y. Variation rs9929218 and risk of the colorectal Cancer and adenomas: A meta-analysis. BMC Cancer 2021; 21:190. [PMID: 33627078 PMCID: PMC7903630 DOI: 10.1186/s12885-021-07871-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 02/02/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUNDS Genome-wide association studies (GWAS) have identified multiple common CRC-related (colorectal cancer) SNPs (single nucleotide polymorphisms) including the Cadherin 1(CDH1) rs9929218 may act by increasing the risk of colorectal cancer, colorectal adenoma, or both. These studies, however, reported inconsistent associations. METHODS To derive a more accurate approximation of the connection, we carried out a meta-analysis of 12 published pieces of research including 11,590 controls and 8192 cases. We used odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations' strength. RESULTS Meta-analysis implied considerable association between CRC and rs9929218 (OR = 1.21, 95%CI 1.04-1.42 for GG versus AA; OR = 1.22, 95%CI 1.05-1.42 for GG/AG versus AA). In the subgroup analyses, significantly increased risks were found among Europeans. CONCLUSIONS In summary, our meta-analysis studies in different populations confirmed that SNP rs9929218 is significantly associated with CRC risk and that this variant may have a greater impact on Europeans.
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Affiliation(s)
- Huiyan Wang
- Liaoning Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042 People’s Republic of China
| | - Dongying Gu
- Department of Oncology, The Affifiliated Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, People’s Republic of China
| | - Miao Yu
- Liaoning Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042 People’s Republic of China
| | - Yanjun Hu
- Liaoning Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042 People’s Republic of China
| | - Zhe Chen
- Liaoning Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042 People’s Republic of China
| | - Xinying Huo
- Department of Oncology, The Affifiliated Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, People’s Republic of China
| | - Tao Yu
- Liaoning Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042 People’s Republic of China
| | - Jinfei Chen
- Department of Oncology, The Affifiliated Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, People’s Republic of China
| | - Yang Zheng
- Liaoning Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province 110042 People’s Republic of China
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23
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Northcutt MJ, Shi Z, Zijlstra M, Shah A, Zheng S, Yen EF, Khan O, Beig MI, Imas P, Vanderloo A, Ansari O, Xu J, Goldstein JL. Polygenic risk score is a predictor of adenomatous polyps at screening colonoscopy. BMC Gastroenterol 2021; 21:65. [PMID: 33579203 PMCID: PMC7881602 DOI: 10.1186/s12876-021-01645-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Single nucleotide polymorphism (SNP)-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. METHODS We randomly selected 1769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of < 0.5, 0.5-1.5, and > 1.5 were categorized as low, average and elevated risk. RESULTS Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, p < 0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, p < 0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, p-trend < 0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, p < 0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps. CONCLUSIONS GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.
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Affiliation(s)
- Michael J. Northcutt
- Division of Gastroenterology, University of Chicago Medicine, NorthShore University HealthSystem, 2650 Ridge Ave, Evanston, IL 60201 USA
| | - Zhuqing Shi
- Program for Personalized Cancer Care, NorthShore University HealthSystem, 1001 University Place, 1001 University Place, Evanston, IL 60201 USA
| | - Michael Zijlstra
- Department of Internal Medicine, University of Chicago Medicine, NorthShore University HealthSystem, 2650 Ridge Ave, Evanston, IL 60201 USA
| | - Ayush Shah
- Department of Internal Medicine, University of Chicago Medicine, NorthShore University HealthSystem, 2650 Ridge Ave, Evanston, IL 60201 USA
| | - Siqun Zheng
- Program for Personalized Cancer Care, NorthShore University HealthSystem, 1001 University Place, 1001 University Place, Evanston, IL 60201 USA
| | - Eugene F. Yen
- Division of Gastroenterology, University of Chicago Medicine, NorthShore University HealthSystem, 2650 Ridge Ave, Evanston, IL 60201 USA
| | - Omar Khan
- Division of Gastroenterology, University of Chicago Medicine, NorthShore University HealthSystem, 2650 Ridge Ave, Evanston, IL 60201 USA
| | - Mohammad Imran Beig
- Department of Clinical Analytics and Health Information Technology, NorthShore University HealthSystem, 4901 Searle Parkway, Skokie, IL 60076 USA
| | - Polina Imas
- Department of Clinical Analytics and Health Information Technology, NorthShore University HealthSystem, 4901 Searle Parkway, Skokie, IL 60076 USA
| | - Adam Vanderloo
- Department of Clinical Analytics and Health Information Technology, NorthShore University HealthSystem, 4901 Searle Parkway, Skokie, IL 60076 USA
| | - Obaid Ansari
- Department of Clinical Analytics and Health Information Technology, NorthShore University HealthSystem, 4901 Searle Parkway, Skokie, IL 60076 USA
| | - Jianfeng Xu
- Program for Personalized Cancer Care, NorthShore University HealthSystem, 1001 University Place, 1001 University Place, Evanston, IL 60201 USA
| | - Jay L. Goldstein
- Division of Gastroenterology, University of Chicago Medicine, NorthShore University HealthSystem, 2650 Ridge Ave, Evanston, IL 60201 USA
- Chicago, IL 60647 USA
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24
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Gargallo-Puyuelo CJ, Lanas Á, Carrera-Lasfuentes P, Ferrández Á, Quintero E, Carrillo M, Alonso-Abreu I, García-González MA. Familial Colorectal Cancer and Genetic Susceptibility: Colorectal Risk Variants in First-Degree Relatives of Patients With Colorectal Cancer. Clin Transl Gastroenterol 2021; 12:e00301. [PMID: 33534415 PMCID: PMC7861964 DOI: 10.14309/ctg.0000000000000301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 12/18/2020] [Indexed: 11/30/2022] Open
Abstract
INTRODUCTION Epidemiological studies estimate that having a first-degree relative (FDR) with colorectal cancer (CRC) increases 2-fold to 3-fold the risk of developing the disease. Because FDRs of CRC patients are more likely to co-inherit CRC risk variants, we aimed to evaluate potential differences in genotype distribution of single nucleotide polymorphisms (SNPs) related to CRC risk between FDRs of patients with nonsyndromic CRC (cases) and individuals with no family history of CRC (controls). METHODS We designed a case-control study comprising 750 cases and 750 Spanish Caucasian controls matched by sex, age, and histological findings after colonoscopy. Genomic DNA from all participants was genotyped for 88 SNPs associated with CRC risk using the MassArray (Sequenom) platform. RESULTS Ten of the 88 SNPs analyzed revealed significant associations (P < 0.05) with a family history of CRC in our population. The most robust associations were found for the rs17094983G>A SNP in the long noncoding RNA LINC01500 (odds ratio = 0.72; 95% confidence interval: 0.58-0.88, log-additive model), and the rs11255841T>A SNP in the long noncoding RNA LINC00709 (odds ratio = 2.04; 95% confidence interval: 1.19-3.51, dominant model). Of interest, the observed associations were in the same direction than those reported for CRC risk. DISCUSSION FDRs of CRC patients show significant differences in genotype distribution of SNPs related to CRC risk as compared to individuals with no family history of CRC. Genotyping of CRC risk variants in FDRs of CRC patients may help to identify subjects at risk that would benefit from stricter surveillance and CRC screening programs.
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Affiliation(s)
- Carla J. Gargallo-Puyuelo
- Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
- University of Zaragoza School of Medicine, Zaragoza, Spain
| | - Ángel Lanas
- Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
- University of Zaragoza School of Medicine, Zaragoza, Spain
- CIBERehd, Zaragoza, Spain
| | | | - Ángel Ferrández
- Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
| | - Enrique Quintero
- Department of Gastroenterology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
- University of La Laguna, School of Medicine, Canary Islands, Spain
| | - Marta Carrillo
- Department of Gastroenterology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Inmaculada Alonso-Abreu
- Department of Gastroenterology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - María Asunción García-González
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain
- CIBERehd, Zaragoza, Spain
- Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain
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25
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He CY, Chen LZ, Wang ZX, Sun LP, Peng JJ, Wu MQ, Wang TM, Li YQ, Yang XH, Zhou DL, Ye ZL, Ma JJ, Li XZ, Zhang PF, Ju HQ, Mo HY, Zhang ZC, Zeng ZL, Shao JY, Jia WH, Cai SJ, Yuan Y, Xu RH. Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study. Genomics 2021; 113:867-873. [PMID: 33545268 DOI: 10.1016/j.ygeno.2021.01.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 01/21/2021] [Accepted: 01/31/2021] [Indexed: 11/25/2022]
Abstract
The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.
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Affiliation(s)
- Cai-Yun He
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Le-Zong Chen
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Zi-Xian Wang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Li-Ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Jun-Jie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Min-Qing Wu
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Tong-Min Wang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Ya-Qi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xin-Hua Yang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Da-Lei Zhou
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Zu-Lu Ye
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Jiang-Jun Ma
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Xi-Zhao Li
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Pei-Fen Zhang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Huai-Qiang Ju
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Hai-Yu Mo
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Zi-Chen Zhang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Zhao-Lei Zeng
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jian-Yong Shao
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Wei-Hua Jia
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
| | - San-Jun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
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Fortini BK, Tring S, Devall MA, Ali MW, Plummer SJ, Casey G. SNPs associated with colorectal cancer at 15q13.3 affect risk enhancers that modulate GREM1 gene expression. Hum Mutat 2021; 42:237-245. [PMID: 33476087 PMCID: PMC7898835 DOI: 10.1002/humu.24166] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 08/12/2020] [Accepted: 11/03/2020] [Indexed: 12/21/2022]
Abstract
Several genome wide association studies of colorectal cancer (CRC) have identified single nucleotide polymorphisms (SNPs) on chromosome 15q13.3 associated with CRC risk. To identify functional variant(s) underlying this association, we investigated SNPs in linkage disequilibrium with the risk‐associated SNP rs4779584 that overlapped regulatory regions/enhancer elements characterized in colon‐related tissues and cells. We identified several SNP‐containing regulatory regions that exhibited enhancer activity in vitro, including one SNP (rs1406389) that correlated with allele‐specific effects on enhancer activity. Deletion of either this enhancer or another enhancer that had previously been reported in this region correlated with decreased expression of GREM1 following CRISPR/Cas9 genome editing. That GREM1 is one target of these enhancers was further supported by an expression quantitative trait loci correlation between rs1406389 and GREM1 expression in the transverse but not sigmoid colon in the Genotype‐Tissue Expression dataset. Taken together, we conclude that the 15q13.3 region contains at least two functional variants that map to distinct enhancers and impact CRC risk through modulation of GREM1 expression.
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Affiliation(s)
| | - Stephanie Tring
- Molecular Genomics Core, University of Southern California, Los Angeles, California, USA
| | - Matthew A Devall
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Mourad Wagdy Ali
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Sarah J Plummer
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA
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Minnee E, Faller WJ. Translation initiation and its relevance in colorectal cancer. FEBS J 2021; 288:6635-6651. [PMID: 33382175 PMCID: PMC9291299 DOI: 10.1111/febs.15690] [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: 10/05/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 01/08/2023]
Abstract
Protein synthesis is one of the most essential processes in every kingdom of life, and its dysregulation is a known driving force in cancer development. Multiple signaling pathways converge on the translation initiation machinery, and this plays a crucial role in regulating differential gene expression. In colorectal cancer, dysregulation of initiation results in translational reprogramming, which promotes the selective translation of mRNAs required for many oncogenic processes. The majority of upstream mutations found in colorectal cancer, including alterations in the WNT, MAPK, and PI3K\AKT pathways, have been demonstrated to play a significant role in translational reprogramming. Many translation initiation factors are also known to be dysregulated, resulting in translational reprogramming during tumor initiation and/or maintenance. In this review, we outline the role of translational reprogramming that occurs during colorectal cancer development and progression and highlight some of the most critical factors affecting the etiology of this disease.
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Affiliation(s)
- Emma Minnee
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - William James Faller
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Sindi IA, Babalghith AO, Tayeb MT, Mufti AH, Naffadi H, Ekram SN, Elhawary EN, Alenezi M, Elhawary NA. Risk of Colorectal Carcinoma May Predispose to the Genetic Variants of the GST, CYP450, and TP53 Genes Among Nonsmokers in the Saudi Community. Int J Gen Med 2021; 14:1311-1323. [PMID: 33883929 PMCID: PMC8055278 DOI: 10.2147/ijgm.s294802] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/25/2021] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Colorectal carcinoma (CRC) represents a considerable public health burden in Saudi Arabia. Several candidate genes and genetic variants have been associated with morbidity and mortality among patients with CRC. We explored whether allelic variants of the GSTM1, GSTT1, CYP450 (rs4646903 and rs1048943), and TP53 (rs1042522) genes predisposed nonsmoking Saudi individuals to increased risk for CRC. PATIENTS AND METHODS DNA from buccal cells of 158 participants (80 with CRC and 78 healthy controls) were analyzed for five SNPs using conventional PCR and TaqMan genotyping assays. The SNPStats software was utilized to choose the best interactive inheritance mode for selected SNPs (https://www.snpstats.net). RESULTS The mean age of diagnosis was 62.4±13.5 years (range, 40-83 years), with those aged 71-80 years and those aged 40-50 years accounting for the most diagnoses (35.7% and 28.6% of diagnosis, respectively). The GSTM1 and TP53 rs1042522 SNPs were associated with CRC (OR= 3.7; P< 0.0001, and OR= 1.6; P= 0.033, respectively). A plausible contribution to CRC was observed for the GSTM1 and TP53 rs1042522 SNPs (x 2 Yates= 14.7; P= 0.00013, and x 2 Yates= 11.2; P= 0.0008, respectively), while the GSTT1 null variant did not affect risk. Heterozygosity in the CYP450 (rs4646903 and rs1048943 SNPs) was associated with a significant risk for CRC. The GSTM1/GSTT1 and CYP450 rs4646903/rs1048943 SNP pairs were in linkage disequilibrium, and the associations were statistically significant (P= 0.01 and P= 4.6x10‒7, respectively). CONCLUSION The GSTM1 and TP53 rs1042522 variants can increase the development of CRC in Saudi nonsmokers. Even the presence of one copy of a variant allele in the CYP1A1 gene can predispose CRC risk. Additional studies should also examine other SNP combinations with lifestyle factors that may help prevent, rather than facilitate, colorectal tumorigenesis.
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Affiliation(s)
- Ikhlas A Sindi
- Department of Biotechnology, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Ikhlas A Sindi Department of Biotechnology, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia Email
| | - Ahmed O Babalghith
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Mecca, 21955, Saudi Arabia
| | - Mohammed T Tayeb
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Mecca, 21955, Saudi Arabia
| | - Ahmad H Mufti
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Mecca, 21955, Saudi Arabia
| | - Hind Naffadi
- Common Science, First Year Deanship, Umm Al-Qura University, Mecca, Saudi Arabia
| | - Samar N Ekram
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Mecca, 21955, Saudi Arabia
- Department of Medical Oncology, King Abdullah City Hospital, Mecca, Saudi Arabia
| | - Ezzeldin N Elhawary
- MS Genomic Medicine Program, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
- Faculty of Biotechnology, October Modern Sciences and Arts University, Giza, Egypt
| | - Munaifah Alenezi
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Mecca, 21955, Saudi Arabia
| | - Nasser A Elhawary
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Mecca, 21955, Saudi Arabia
- Department of Genetics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
- Correspondence: Nasser A Elhawary Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 57543, Mecca, 21955, Saudi ArabiaTel +966 55 369 2180 Email
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29
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Hao P, Yu J, Ward R, Liu Y, Hao Q, An S, Xu T. Eukaryotic translation initiation factors as promising targets in cancer therapy. Cell Commun Signal 2020; 18:175. [PMID: 33148274 PMCID: PMC7640403 DOI: 10.1186/s12964-020-00607-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 06/01/2020] [Indexed: 02/08/2023] Open
Abstract
The regulation of the translation of messenger RNA (mRNA) in eukaryotic cells is critical for gene expression, and occurs principally at the initiation phase which is mainly regulated by eukaryotic initiation factors (eIFs). eIFs are fundamental for the translation of mRNA and as such act as the primary targets of several signaling pathways to regulate gene expression. Mis-regulated mRNA expression is a common feature of tumorigenesis and the abnormal activity of eIF complexes triggered by upstream signaling pathways is detected in many tumors, leading to the selective translation of mRNA encoding proteins involved in tumorigenesis, metastasis, or resistance to anti-cancer drugs, and making eIFs a promising therapeutic target for various types of cancers. Here, we briefly outline our current understanding of the biology of eIFs, mainly focusing on the effects of several signaling pathways upon their functions and discuss their contributions to the initiation and progression of tumor growth. An overview of the progress in developing agents targeting the components of translation machinery for cancer treatment is also provided.
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