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Yan L, He Q, Verma SP, Zhang X, Giel AS, Maj C, Graz K, Naderi E, Chen J, Ali MW, Gharahkhani P, Shu X, Offit K, Shah PM, Gerdes H, Molena D, Srivastava A, MacGregor S, Palles C, Thieme R, Vieth M, Gockel I, Vaughan TL, Schumacher J, Buas MF. Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma. HGG ADVANCES 2025; 6:100399. [PMID: 39755942 PMCID: PMC11815673 DOI: 10.1016/j.xhgg.2025.100399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/30/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025] Open
Abstract
Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ∼30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (1) known/plausible links to BE/EAC pathogenesis (n = 493) or (2) prior evidence of biological interactions (n = 4,196). Approximately 75 × 106 SNP×SNP interactions were screened via hierarchical group lasso (glinternet) using BEACON GWAS data. The top ∼2,000 interactions retained in each scan were prioritized using p values from single logistic models. Identical scans were repeated among males only (78%), with two independent GWAS datasets used for replication. In overall and male-specific primary replications, 11 of 187 and 20 of 191 interactions satisfied p < 0.05, respectively. The strongest evidence for secondary replication was for rs17744726×rs3217992 among males, with consistent directionality across all cohorts (Pmeta = 2.19 × 10-8); rs3217992 "T" was associated with reduced risk only in individuals homozygous for rs17744726 "G." Rs3217992 maps to the CDKN2B 3' UTR and reportedly disrupts microRNA-mediated repression. Rs17744726 maps to an intronic enhancer region in BLK. Through in silico prioritization and experimental validation, we identified a nearby proxy variant (rs4841556) as a functional modulator of enhancer activity. Enhancer-gene mapping and eQTLs implicated BLK and FAM167A as targets. The first systematic G×G investigation in BE/EAC, this study uncovers differential risk associations for CDKN2B variation by BLK genotype, suggesting novel biological dependency between two risk loci encoding key mediators of tumor suppression and inflammation.
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Affiliation(s)
- Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Qianchuan He
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Shiv P Verma
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xu Zhang
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ann-Sophie Giel
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Carlo Maj
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Kathryn Graz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elnaz Naderi
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jianhong Chen
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Mourad Wagdy Ali
- Department of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Puya Gharahkhani
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Xiang Shu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Offit
- Clinical Genetics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Pari M Shah
- Gastroenterology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hans Gerdes
- Gastroenterology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Daniela Molena
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amitabh Srivastava
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stuart MacGregor
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Claire Palles
- Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Thomas L Vaughan
- 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
| | | | - Matthew F Buas
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Barghout SH, Meti N, Chotai S, Kim CJH, Patel D, Brown MC, Hueniken K, Zhan LJ, Raptis S, Al-Agha F, Deutschman C, Grant B, Pienkowski M, Moriarty P, de Almeida J, Goldstein DP, Bratman SV, Shepherd FA, Tsao MS, Freedman AN, Xu W, Liu G. Adaptive Universal Principles for Real-world Observational Studies (AUPROS): an approach to designing real-world observational studies for clinical, epidemiologic, and precision oncology research. Br J Cancer 2025; 132:139-153. [PMID: 39572762 PMCID: PMC11746990 DOI: 10.1038/s41416-024-02899-x] [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: 07/30/2024] [Revised: 10/22/2024] [Accepted: 10/28/2024] [Indexed: 01/22/2025] Open
Abstract
The field of precision oncology has witnessed several advances that stimulated the development of new clinical trial designs and the emergence of real-world data (RWD) as an important resource for evidence generation in healthcare decision-making. Here, we highlight our experience with an innovative approach to a set of Adaptive, Universal Principles for Real-world Observational Studies (AUPROS). To demonstrate the utility of these principles, we used a mixed-methods approach to assess three studies that follow AUPROS at Princess Margaret Cancer Centre: (1) Molecular Epidemiology of ThorAcic Lesions (METAL), (2) Translational Head And NecK Study (THANKS), and (3) CAnadian CAncers With Rare Molecular Alterations (CARMA; NCT04151342). We performed resource assessments, stakeholder-directed surveys and discussions, analysis of funding, research output, collaborations, and a Strengths-Weaknesses-Opportunities-Threats (SWOT) analysis. Based on these analyses, AUPROS is an approach that is applicable to a wide range of observational study designs. The universality of AUPROS allows for multi-purpose analyses of various RWD, and the adaptive nature creates opportunities for multi-source funding and collaborations. Following AUPROS can offer cost and logistical benefits and may lead to increased research productivity. Several challenges were identified pertinent to ethics approvals, sustainability, complex coordination, and data quality that require local adaptation of these principles.
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Affiliation(s)
- Samir H Barghout
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Nicholas Meti
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Simren Chotai
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Royal College of Surgeons, Dublin, Ireland
| | - Christina J H Kim
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Division of General Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Devalben Patel
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - M Catherine Brown
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Katrina Hueniken
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Luna J Zhan
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Stavroula Raptis
- Applied Health Research Centre, Unity Health, Toronto, ON, Canada
| | - Faisal Al-Agha
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | | | - Benjamin Grant
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Martha Pienkowski
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | | | - John de Almeida
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Otolaryngology-Head and Neck Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - David P Goldstein
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Otolaryngology-Head and Neck Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Scott V Bratman
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Frances A Shepherd
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Ming S Tsao
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Andrew N Freedman
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD, USA
| | - Wei Xu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Geoffrey Liu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
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Barchi A, Dell’Anna G, Massimino L, Mandarino FV, Vespa E, Viale E, Passaretti S, Annese V, Malesci A, Danese S, Ungaro F. Unraveling the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma: the "omics" era. Front Oncol 2025; 14:1458138. [PMID: 39950103 PMCID: PMC11821489 DOI: 10.3389/fonc.2024.1458138] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 12/10/2024] [Indexed: 02/16/2025] Open
Abstract
Barrett's esophagus (BE) represents a pre-cancerous condition that is characterized by the metaplastic conversion of the squamous esophageal epithelium to a columnar intestinal-like phenotype. BE is the consequence of chronic reflux disease and has a potential progression burden to esophageal adenocarcinoma (EAC). The pathogenesis of BE and EAC has been extensively studied but not completely understood, and it is based on two main hypotheses: "transdifferentiation" and "transcommitment". Omics technologies, thanks to the potentiality of managing huge amounts of genetic and epigenetic data, sequencing the whole genome, have revolutionized the understanding of BE carcinogenesis, paving the way for biomarker development helpful in early diagnosis and risk progression assessment. Genomics and transcriptomics studies, implemented with the most advanced bioinformatics technologies, have brought to light many new risk loci and genomic alterations connected to BE and its progression to EAC, further exploring the complex pathogenesis of the disease. Early mutations of the TP53 gene, together with late aberrations of other oncosuppressor genes (SMAD4 or CKND2A), represent a genetic driving force behind BE. Genomic instability, nonetheless, is the central core of the disease. The implementation of transcriptomic and proteomic analysis, even at the single-cell level, has widened the horizons, complementing the genomic alterations with their transcriptional and translational bond. Increasing interest has been gathered around small circulating genetic traces (circulating-free DNA and micro-RNAs) with a potential role as blood biomarkers. Epigenetic alterations (such as hyper or hypo-methylation) play a meaningful role in esophageal carcinogenesis as well as the study of the tumor micro-environment, which has led to the development of novel immunological therapeutic options. Finally, the esophageal microbiome could be the protagonist to be investigated, deepening our understanding of the subtle association between the host microbiota and tumor development.
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Affiliation(s)
- Alberto Barchi
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Giuseppe Dell’Anna
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, Milan, Italy
| | - Luca Massimino
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
| | | | - Edoardo Vespa
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Edi Viale
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Sandro Passaretti
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Vito Annese
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, Milan, Italy
- Università Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
| | - Alberto Malesci
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS Policlinico San Donato, Milan, Italy
| | - Silvio Danese
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
| | - Federica Ungaro
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
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Wickramasinghe N, Devanarayana NM. Unveiling the intricacies: Insight into gastroesophageal reflux disease. World J Gastroenterol 2025; 31:98479. [PMID: 39777237 PMCID: PMC11684178 DOI: 10.3748/wjg.v31.i1.98479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/26/2024] [Accepted: 11/11/2024] [Indexed: 12/09/2024] Open
Abstract
Gastroesophageal reflux disease (GERD) poses a substantial global health challenge, with prevalence rates exhibiting geographical variation. Despite its widespread recognition, the exact prevalence and associated risk factors remain elusive. This article comprehensively analyzed the global burden of GERD, shedding light on its risk factors, underlying pathophysiological mechanisms, current diagnostic modalities, evolving management strategies tailored to diverse patient profiles, and complex determinants contributing to treatment failures. A deeper comprehension of GERD is achieved by dissecting these intricate facets, paving the way for enhanced clinical management and improved patient outcomes.
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Affiliation(s)
- Nilanka Wickramasinghe
- Department of Physiology, Faculty of Medicine, University of Colombo, Colombo 00800, Western Province, Sri Lanka
| | - Niranga Manjuri Devanarayana
- Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama 11010, Western Province, Sri Lanka
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Jalali P, Yaghoobi A, Rezaee M, Zabihi MR, Piroozkhah M, Aliyari S, Salehi Z. Decoding common genetic alterations between Barrett's esophagus and esophageal adenocarcinoma: A bioinformatics analysis. Heliyon 2024; 10:e31194. [PMID: 38803922 PMCID: PMC11128929 DOI: 10.1016/j.heliyon.2024.e31194] [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: 11/08/2023] [Revised: 05/12/2024] [Accepted: 05/13/2024] [Indexed: 05/29/2024] Open
Abstract
Background Esophageal adenocarcinoma (EAC) is a common cancer with a poor prognosis in advanced stages. Therefore, early EAC diagnosis and treatment have gained attention in recent decades. It has been found that various pathological changes, particularly Barrett's Esophagus (BE), can occur in the esophageal tissue before the development of EAC. In this study, we aimed to identify the molecular contributor in BE to EAC progression by detecting the essential regulatory genes that are differentially expressed in both BE and EAC. Materials and methods We conducted a comprehensive bioinformatics analysis to detect BE and EAC-associated genes. The common differentially expressed genes (DEGs) and common single nucleotide polymorphisms (SNPs) were detected using the GEO and DisGeNET databases, respectively. Then, hub genes and the top modules within the protein-protein interaction network were identified. Moreover, the co-expression network of the top module by the HIPPIE database was constructed. Additionally, the gene regulatory network was constructed based on miRNAs and circRNAs. Lastly, we inspected the DGIdb database for possible interacted drugs. Results Our microarray dataset analysis identified 92 common DEGs between BE and EAC with significant enrichment in skin and epidermis development genes. The study also identified 22 common SNPs between BE and EAC. The top module of PPI network analysis included SCEL, KRT6A, SPRR1A, SPRR1B, SPRR3, PPL, SPRR2B, EVPL, and CSTA. We constructed a ceRNA network involving three specific mRNAs, 23 miRNAs, and 101 selected circRNAs. According to the results from the DGIdb database, TD101 was found to interact with the KRT6A gene. Conclusion The present study provides novel potential candidate genes that may be involved in the molecular association between Esophageal adenocarcinoma and Barrett's Esophagus, resulting in developing the diagnostic tools and therapeutic targets to prevent progression of BE to EAC.
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Affiliation(s)
- Pooya Jalali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Yaghoobi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Malihe Rezaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zabihi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Piroozkhah
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahram Aliyari
- Division of Applied Bioinformatics, German Cancer Research Center DKFZ Heidelberg, Iran
| | - Zahra Salehi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
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Muhammad Nawawi KN, El‐Omar EM, Ali RA. Screening, Surveillance, and Prevention of Esophageal and Gastric Cancers. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:42-62. [DOI: 10.1002/9781119756422.ch3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Arshad HMS, Farooq U, Cheema A, Arshad A, Masood M, Vega KJ. Disparities in esophageal cancer incidence and esophageal adenocarcinoma mortality in the United States over the last 25-40 years. World J Gastrointest Endosc 2023; 15:715-724. [PMID: 38187915 PMCID: PMC10768036 DOI: 10.4253/wjge.v15.i12.715] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/17/2023] [Accepted: 11/13/2023] [Indexed: 12/15/2023] Open
Abstract
BACKGROUND Esophageal carcinoma presents as 2 types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) with the frequency of both changing in the United States (US).
AIM To investigate EAC/ESCC incidence time trends among the 3 main US racial groups and investigate trends in US EAC survival by ethnicity.
METHODS Twenty-five years (1992-2016) of data from SEER 13 program was analyzed to compare incidence trends in EAC and ESCC between non-Hispanic whites (nHW), non-Hispanic Blacks (nHB) and Hispanics (Hisp) using SEERStat®. In addition, SEER 18 data, from 1975-2015, on EAC in the US was analyzed to evaluate racial disparities in incidence and survival using SEERStat® and Ederer II method.
RESULTS In the 3 major US ethnic groups, age-adjusted incidence of ESCC has declined while EAC has continued to rise from 1992-2016. Of note, in Hisp, the EAC incidence rate increased while ESCC decreased from 1992 to 2016, resulting in EAC as the predominant esophageal cancer subtype in this group since 2011, joining nHW. Furthermore, although ESCC remains the predominant tumor in nHB, the difference between ESCC and EAC has narrowed dramatically over 25 years. EAC survival probabilities were worse in all minority groups compared to nHw.
CONCLUSION Hisp have joined nHW as US ethnic groups more likely to have EAC than ESCC. Of note, EAC incidence in nHB is increasing at the highest rate nationally. Despite lower EAC incidence in all minority groups compared to nHW, these populations have decreased survival compared to nHW.
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Affiliation(s)
- Hafiz Muhammad Sharjeel Arshad
- Division of Gastroenterology & Hepatology, Augusta University - Medical College of Georgia, Augusta, GA 30912, United States
| | - Umer Farooq
- Department of Internal Medicine, Loyola Medicine/MacNeil Hospital, Berwyn, IL 60402, United States
| | - Ayesha Cheema
- Division of Gastroenterology & Hepatology, Augusta University - Medical College of Georgia, Augusta, GA 30912, United States
| | - Ayesha Arshad
- Department of Medicine, Fatima Memorial Medical College, Lahore 54000, Punjab, Pakistan
| | - Muaaz Masood
- Department of Medicine, Augusta University - Medical College of Georgia, Augusta, GA 30912, United States
| | - Kenneth J Vega
- Division of Gastroenterology & Hepatology, Augusta University - Medical College of Georgia, Augusta, GA 30912, United States
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Wang X, Tian R, Zong X, Jeon MS, Luo J, Colditz GA, Wang JS, Tsilidis KK, Ju YES, Govindan R, Puri V, Cao Y. Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer. Cancer Epidemiol Biomarkers Prev 2023; 32:1079-1086. [PMID: 37195052 PMCID: PMC10525008 DOI: 10.1158/1055-9965.epi-23-0101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/16/2023] [Accepted: 05/11/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND Risk factors contributing to more than 10-fold increase in esophageal cancer in the last 50 years remain underexplored. We aim to examine the associations of sleep behaviors with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). METHODS We prospectively assessed the associations between sleep behaviors (chronotype, duration, daytime napping, daytime sleepiness, snoring, and insomnia) and EAC and ESCC risk in 393,114 participants in the UK Biobank (2006-2016). Participants with 0, 1, and ≥2 unhealthy behaviors, including sleep <6 or >9 h/d, daytime napping, and usual daytime sleepiness were classified as having a good, intermediate, and poor sleep. For EAC, we also examined interactions with polygenic risk score (PRS). Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS We documented 294 incident EAC and 95 ESCC. Sleep >9 h/d (HR, 2.05; 95% CI, 1.18-3.57) and sometimes daytime napping (HR, 1.36; 95% CI, 1.06-1.75) were individually associated with increased EAC risk. Compared with individuals with good sleep, those with intermediate sleep had a 47% (HR, 1.47; 95% CI, 1.13-1.91) increased EAC risk, and those with poor sleep showed an 87% (HR, 1.87; 95% CI, 1.24-2.82) higher risk (Ptrend < 0.001). The elevated risks for EAC were similar within strata of PRS (Pinteraction = 0.884). Evening chronotype was associated with elevated risk of ESCC diagnosed after 2 years of enrollment (HR, 2.79; 95% CI, 1.32-5.88). CONCLUSIONS Unhealthy sleep behaviors were associated with an increased risk of EAC, independent of genetic risk. IMPACT Sleep behaviors may serve as modifiable factors for the prevention of EAC.
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Affiliation(s)
- Xiaoyan Wang
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, USA
- Brown School, Washington University in St. Louis, St. Louis, USA
| | - Ruiyi Tian
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, USA
- Brown School, Washington University in St. Louis, St. Louis, USA
| | - Xiaoyu Zong
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, USA
| | - Myung Sik Jeon
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, USA
| | - Jingqin Luo
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, USA
| | - Graham A. Colditz
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, USA
| | - Jean S. Wang
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, 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
| | - Yo-El S. Ju
- Center on Biological Rhythms and Sleep (COBRAS), Washington University School of Medicine, St. Louis, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, USA
- Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA
| | - Ramaswamy Govindan
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, USA
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, USA
| | - Varun Puri
- Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, USA
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, USA
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, USA
- Center on Biological Rhythms and Sleep (COBRAS), Washington University School of Medicine, St. Louis, USA
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Li X, Wang Y, Min Q, Zhang W, Teng H, Li C, Zhang K, Shi L, Wang B, Zhan Q. Comparative transcriptome characterization of esophageal squamous cell carcinoma and adenocarcinoma. Comput Struct Biotechnol J 2023; 21:3841-3853. [PMID: 37564101 PMCID: PMC10410469 DOI: 10.1016/j.csbj.2023.07.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 07/20/2023] [Accepted: 07/22/2023] [Indexed: 08/12/2023] Open
Abstract
Background Esophageal cancers are primarily categorized as esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). While various (epi) genomic alterations associated with tumor development in ESCC and EAC have been documented, a comprehensive comparison of the transcriptomes in these two cancer subtypes remains lacking. Methods We collected 551 gene expression profiles from publicly available sources, including normal, ESCC, and EAC tissues or cell lines. Subsequently, we conducted a systematic analysis to compare the transcriptomes of these samples at various levels, including gene expression, promoter activity, alternative splicing (AS), alternative polyadenylation (APA), and gene fusion. Results Seven distinct cluster gene expression patterns were identified among the differentially expressed genes in normal, ESCC, and EAC tissues. These patterns were enriched in the PI3K-Akt signaling pathway and the activation of extracellular matrix organization and exhibited repression of epidermal development. Notably, we observed additional genes or unique expression levels enriched in these shared pathways and biological processes related to tumor development and immune activation. In addition to the differentially expressed genes, there was an enrichment of lncRNA co-expression networks and downregulation of promoter activity associated with the repression of epidermal development in both ESCC and EAC. This indicates a common feature between these two cancer subtypes. Furthermore, differential AS and APA patterns in ESCC and EAC appear to partially affect the expression of host genes associated with bacterial or viral infections in these subtypes. No gene fusions were observed between ESCC and EAC, thus highlighting the distinct molecular mechanisms underlying these two cancer subtypes. Conclusions We conducted a comprehensive comparison of ESCC and EAC transcriptomes and uncovered shared and distinct transcriptomic signatures at multiple levels. These findings suggest that ESCC and EAC may exhibit common and unique mechanisms involved in tumorigenesis.
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Affiliation(s)
- Xianfeng Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10# Changjiang Branch Road, Yuzhong District, Chongqing 400042, People's Republic of China
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, People's Republic of China
- Jinfeng Laboratory, Chongqing 401329, People's Republic of China
| | - Yan Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Qingjie Min
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Weimin Zhang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Huajing Teng
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chao Li
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China
| | - Kun Zhang
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325035, China
| | - Leisheng Shi
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Bin Wang
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10# Changjiang Branch Road, Yuzhong District, Chongqing 400042, People's Republic of China
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, People's Republic of China
- Jinfeng Laboratory, Chongqing 401329, People's Republic of China
| | - Qimin Zhan
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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10
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Schröder J, Chegwidden L, Maj C, Gehlen J, Speller J, Böhmer AC, Borisov O, Hess T, Kreuser N, Venerito M, Alakus H, May A, Gerges C, Schmidt T, Thieme R, Heider D, Hillmer AM, Reingruber J, Lyros O, Dietrich A, Hoffmeister A, Mehdorn M, Lordick F, Stocker G, Hohaus M, Reim D, Kandler J, Müller M, Ebigbo A, Fuchs C, Bruns CJ, Hölscher AH, Lang H, Grimminger PP, Dakkak D, Vashist Y, May S, Görg S, Franke A, Ellinghaus D, Galavotti S, Veits L, Weismüller J, Dommermuth J, Benner U, Rösch T, Messmann H, Schumacher B, Neuhaus H, Schmidt C, Wissinowski TT, Nöthen MM, Dong J, Ong JS, Buas MF, Thrift AP, Vaughan TL, Tomlinson I, Whiteman DC, Fitzgerald RC, Jankowski J, Vieth M, Mayr A, Gharahkhani P, MacGregor S, Gockel I, Palles C, Schumacher J. GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level. Gut 2023; 72:612-623. [PMID: 35882562 DOI: 10.1136/gutjnl-2021-326698] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 07/07/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.
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Affiliation(s)
- Julia Schröder
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Laura Chegwidden
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Carlo Maj
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Jan Gehlen
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Jan Speller
- Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), Medical Faculty, University of Bonn, Bonn, Germany
| | - Anne C Böhmer
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Oleg Borisov
- Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Timo Hess
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Hakan Alakus
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Andrea May
- Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Clinic Wiesbaden, Wiesbaden, Germany
| | - Christian Gerges
- Department of Internal Medicine II, Evangelisches Krankenhaus Dusseldorf, Dusseldorf, Germany
| | - Thomas Schmidt
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Rene Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Dominik Heider
- Department of Mathematics and Computer Science, University of Marburg, Marburg, Germany
| | - Axel M Hillmer
- Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University Hospital Cologne, Cologne, Germany
| | - Julian Reingruber
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Orestis Lyros
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Arne Dietrich
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | | | - Matthias Mehdorn
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Florian Lordick
- University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany
| | - Gertraud Stocker
- University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany
| | - Michael Hohaus
- Department for General and Visceral Surgery, Städt. Klinikum Dresden Friedrichstadt, Dresden, Germany
| | - Daniel Reim
- Department of Surgery, Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, München, Germany
| | - Jennis Kandler
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Dusseldorf, Medical Faculty of Heinrich Heine University Dusseldorf, Dusseldorf, Germany
| | - Michaela Müller
- Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany
| | - Alanna Ebigbo
- Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany
| | - Claudia Fuchs
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Christiane J Bruns
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Arnulf H Hölscher
- Department for General, Visceral and Trauma Surgery, Elisabeth-Krankenhaus-Essen GmbH, Essen, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Peter P Grimminger
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Dani Dakkak
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital Essen, Essen, Germany
| | | | - Sandra May
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Siegfried Görg
- Institute of Transfusion Medicine, University Hospital of Schleswig-Holstein, Lübeck/Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Sara Galavotti
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Lothar Veits
- Institute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany
| | | | | | - Udo Benner
- Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany
| | - Thomas Rösch
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Helmut Messmann
- Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital Essen, Essen, Germany
| | - Horst Neuhaus
- Department of Internal Medicine II, Evangelisches Krankenhaus Dusseldorf, Dusseldorf, Germany
| | - Carsten Schmidt
- Medical Clinic II (Gastroenterology, Hepatology, Endocrinology, Diabetology and Infektiology), Klinikum Fulda, University Medicine Marburg-Campus Fulda, Fulda, Germany
- Medical Faculty, Friedrich Schiller University Jena, Jena, Germany
| | | | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Jing Dong
- Division of Hematology and Oncology, Department of Medicine, Cancer Center, and Genomic Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jue-Sheng Ong
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Matthew F Buas
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Ian Tomlinson
- Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK
| | - David C Whiteman
- Cancer Control, Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Rebecca Claire Fitzgerald
- Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, Cambridgeshire, UK
| | - Janusz Jankowski
- Comprehensive Clinical Trials Unit, University College London, London, UK
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany
| | - Andreas Mayr
- Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), Medical Faculty, University of Bonn, Bonn, Germany
| | - Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
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11
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Zheng Y, Niu X, Wei Q, Li Y, Li L, Zhao J. Familial Esophageal Cancer in Taihang Mountain, China: An Era of Personalized Medicine Based on Family and Population Perspective. Cell Transplant 2022; 31:9636897221129174. [PMID: 36300368 PMCID: PMC9618747 DOI: 10.1177/09636897221129174] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
In the Taihang Mountain areas, known as the “esophageal cancer zone” in China, the incidence of esophageal cancer (ESCA) ranks the first in the country and shows a familial and regional clustering trend. Taihang Mountain areas are located in a mountainous area, with inconvenient transportation, limited living conditions, unbalanced diet, and poor nutrition. Ninety percent of the pathological types of ESCA in Taihang Mountain areas are squamous cell carcinoma, among which the risk factors have not been well understood. These areas are usually remote villages and mountains with low population mobility, large family members, similar environmental factors, and a clear and stable genetic background. Therefore, according to the current situation, second-generation sequencing and multigroup analysis technology are used to analyze the familial ESCA patients; disease-related genetic variation are located; and then disease-related susceptibility genes associated with ESCA are screened and analyzed. Health education, tobacco control, endoscopic screening, and other health management projects for suspected and high-risk patients in areas with a high incidence of ESCA can be carried out for screening and early diagnosis, and the incidence of ESCA in Taihang Mountain areas can be reduced. A comprehensive continuous care pattern based on traditional medical nursing to track, monitor, evaluate, and intervene with patients diagnosed with ESCA to facilitate them with medications guidance, dietary guidance, and timely health problem-solving is established. Furthermore, statistical analysis of epidemiology, gene sequencing, and family genetics information can be performed on patients with ESCA in the Taihang Mountains areas to clarify the relationship between genetic phenotype and genotype during the occurrence of ESCA.
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Affiliation(s)
- Yuanyuan Zheng
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyu Niu
- Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Qian Wei
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yijing Li
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lifeng Li
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Biological Cell Therapy Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Zhao
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Jie Zhao, National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
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12
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Uno K, Koike T, Hatta W, Saito M, Tanabe M, Masamune A. Development of Advanced Imaging and Molecular Imaging for Barrett's Neoplasia. Diagnostics (Basel) 2022; 12:2437. [PMID: 36292126 PMCID: PMC9600913 DOI: 10.3390/diagnostics12102437] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/04/2022] [Indexed: 11/17/2022] Open
Abstract
Barrett esophagus (BE) is a precursor to a life-threatening esophageal adenocarcinoma (EAC). Surveillance endoscopy with random biopsies is recommended for early intervention against EAC, but its adherence in the clinical setting is poor. Dysplastic lesions with flat architecture and patchy distribution in BE are hardly detected by high-resolution endoscopy, and the surveillance protocol entails issues of time and labor and suboptimal interobserver agreement for diagnosing dysplasia. Therefore, the development of advanced imaging technologies is necessary for Barrett's surveillance. Recently, non-endoscopic or endoscopic technologies, such as cytosponge, endocytoscopy, confocal laser endomicroscopy, autofluorescence imaging, and optical coherence tomography/volumetric laser endomicroscopy, were developed, but most of them are not clinically available due to the limited view field, expense of the equipment, and significant time for the learning curve. Another strategy is focused on the development of molecular biomarkers, which are also not ready to use. However, a combination of advanced imaging techniques together with specific biomarkers is expected to identify morphological abnormalities and biological disorders at an early stage in the surveillance. Here, we review recent developments in advanced imaging and molecular imaging for Barrett's neoplasia. Further developments in multiple biomarker panels specific for Barrett's HGD/EAC include wide-field imaging systems for targeting 'red flags', a high-resolution imaging system for optical biopsy, and a computer-aided diagnosis system with artificial intelligence, all of which enable a real-time and accurate diagnosis of dysplastic BE in Barrett's surveillance and provide information for precision medicine.
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Affiliation(s)
- Kaname Uno
- Division of Gastroenterology, Tohoku University Hospital, Sendai 981-8574, Japan
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13
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Wang X, Gharahkhani P, Levine DM, Fitzgerald RC, Gockel I, Corley DA, Risch HA, Bernstein L, Chow WH, Onstad L, Shaheen NJ, Lagergren J, Hardie LJ, Wu AH, Pharoah PDP, Liu G, Anderson LA, Iyer PG, Gammon MD, Caldas C, Ye W, Barr H, Moayyedi P, Harrison R, Watson RGP, Attwood S, Chegwidden L, Love SB, MacDonald D, deCaestecker J, Prenen H, Ott K, Moebus S, Venerito M, Lang H, Mayershofer R, Knapp M, Veits L, Gerges C, Weismüller J, Reeh M, Nöthen MM, Izbicki JR, Manner H, Neuhaus H, Rösch T, Böhmer AC, Hölscher AH, Anders M, Pech O, Schumacher B, Schmidt C, Schmidt T, Noder T, Lorenz D, Vieth M, May A, Hess T, Kreuser N, Becker J, Ell C, Tomlinson I, Palles C, Jankowski JA, Whiteman DC, MacGregor S, Schumacher J, Vaughan TL, Buas MF, Dai JY. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2022; 31:1735-1745. [PMID: 35709760 PMCID: PMC9444939 DOI: 10.1158/1055-9965.epi-22-0096] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/13/2022] [Accepted: 06/13/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.
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Affiliation(s)
- Xiaoyu Wang
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Puya Gharahkhani
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - David M. Levine
- Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington, USA
| | - Rebecca C. Fitzgerald
- Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Douglas A. Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
- San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, USA
| | - Harvey A. Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
| | - Leslie Bernstein
- Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, USA
| | - Wong-Ho Chow
- Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, USA
| | - Lynn Onstad
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Nicholas J. Shaheen
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
- School of Cancer and Pharmaceutical Sciences, King’s College London
| | | | - Anna H. Wu
- Department of Population and Public Health Sciences, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Paul D. P. Pharoah
- Department of Oncology, University of Cambridge, Cambridge, UK
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Geoffrey Liu
- Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada
| | - Lesley A. Anderson
- Department of Epidemiology and Public Health, Queen's University of Belfast, Royal Group of Hospitals, Northern Ireland
| | - Prasad G. Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Marilie D. Gammon
- Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Carlos Caldas
- Cancer Research UK, Cambridge Institute, Cambridge, UK
| | - Weimin Ye
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Hugh Barr
- Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK
| | - Paul Moayyedi
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Rebecca Harrison
- Department of Pathology, Leicester Royal Infirmary, Leicester, UK
| | - RG Peter Watson
- Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK
| | - Stephen Attwood
- Department of General Surgery, North Tyneside General Hospital, North Shields, UK
| | - Laura Chegwidden
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
| | - Sharon B. Love
- Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit, Oxford, UK
| | - David MacDonald
- Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - John deCaestecker
- Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK
| | - Hans Prenen
- Oncology Department, University Hospital Antwerp, Edegem, Belgium
| | - Katja Ott
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Susanne Moebus
- Institute for Urban Public Health, University Hospitals, University of Duisburg-Essen, Essen, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | | | - Michael Knapp
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
| | - Lothar Veits
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Klinikum Bayreuth, Bayreuth, Germany
| | - Christian Gerges
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany
| | | | - Matthias Reeh
- Department of General, Visceral and Thoracic Surgery, Asklepios Harzklinik Goslar, Goslar, Germany
| | - Markus M. Nöthen
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Jakob R. Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic. University Medical Center Hamburg-Eppendorf. Hamburg. Germany
| | - Hendrik Manner
- Department of Internal Medicine II, Frankfurt Hoechst Hospital, Frankfurt, Germany
| | - Horst Neuhaus
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Thomas Rösch
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Anne C. Böhmer
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Arnulf H. Hölscher
- Clinic for General, Visceral and Trauma Surgery, Contilia Center for Esophageal Diseases. Elisabeth Hospital Essen, Germany
| | - Mario Anders
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
- Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany
| | - Oliver Pech
- Department of Gastroenterology and Interventional Endoscopy, St. John of God Hospital, Regensburg, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | - Claudia Schmidt
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Tania Noder
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Dietmar Lorenz
- Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Klinikum Bayreuth, Bayreuth, Germany
| | - Andrea May
- Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Klinik, Wiesbaden, Germany
| | - Timo Hess
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Jessica Becker
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Christian Ell
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Ian Tomlinson
- Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, UK
| | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | | | - David C. Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Stuart MacGregor
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | | | - Thomas L. Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, USA
| | - Matthew F. Buas
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263 USA
| | - James Y. Dai
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington, USA
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14
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Souza RF, Spechler SJ. Mechanisms and pathophysiology of Barrett oesophagus. Nat Rev Gastroenterol Hepatol 2022; 19:605-620. [PMID: 35672395 DOI: 10.1038/s41575-022-00622-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2022] [Indexed: 01/10/2023]
Abstract
Barrett oesophagus, in which a metaplastic columnar mucosa that can predispose individuals to cancer development lines a portion of the distal oesophagus, is the only known precursor of oesophageal adenocarcinoma, the incidence of which has increased profoundly over the past several decades. Most evidence suggests that Barrett oesophagus develops from progenitor cells at the oesophagogastric junction that proliferate and undergo epithelial-mesenchymal transition as part of a wound-healing process that replaces oesophageal squamous epithelium damaged by gastroesophageal reflux disease (GERD). GERD also seems to induce reprogramming of key transcription factors in the progenitor cells, resulting in the development of the specialized intestinal metaplasia that is characteristic of Barrett oesophagus, probably through an intermediate step of metaplasia to cardiac mucosa. Genome-wide association studies suggest that patients with GERD who develop Barrett oesophagus might have an inherited predisposition to oesophageal metaplasia and that there is a shared genetic susceptibility to Barrett oesophagus and to several of its risk factors (such as GERD, obesity and cigarette smoking). In this Review, we discuss the mechanisms, pathophysiology, genetic predisposition and cells of origin of Barrett oesophagus, and opine on the clinical implications and future research directions.
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Affiliation(s)
- Rhonda F Souza
- Division of Gastroenterology, Center for Oesophageal Diseases, Baylor University Medical Center, Dallas, TX, USA. .,Center for Oesophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA.
| | - Stuart J Spechler
- Division of Gastroenterology, Center for Oesophageal Diseases, Baylor University Medical Center, Dallas, TX, USA.,Center for Oesophageal Research, Baylor Scott & White Research Institute, Dallas, TX, USA
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15
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Ma SZ, Chen HX, Liang ZD, Qi XS. Risk factors for Barrett's esophagus: Recent advances. Shijie Huaren Xiaohua Zazhi 2022; 30:605-613. [DOI: 10.11569/wcjd.v30.i14.605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) is the most common malignant tumor of the esophagus in the West. During the past few decades, its morbidity has been increasing in China. Barrett's esophagus (BE) is defined as the replacement of normal squamous epithelium in the lower esophagus by metaplasia of columnar epithelium. BE is closely related to the occurrence of EAC. Knowledge regarding the risk factors for the occurrence and development of BE is of great significance for early screening and diagnosis of BE and prevention of EAC. In this paper, we review the clinical, demographics-related, lifestyle-related, and medications-related risk factors for BE to provide more valuable scientific evidence for the prevention and treatment of BE.
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Affiliation(s)
- Shao-Ze Ma
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China,Graduate School of Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Hong-Xin Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China,Graduate School of Liaoning University of Traditional Chinese Medicine, Shenyang 110031, Liaoning Province, China
| | - Zhen-Dong Liang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xing-Shun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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16
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Ali MW, Chen J, Yan L, Wang X, Dai JY, Vaughan TL, Casey G, Buas MF. A risk variant for Barrett's esophagus and esophageal adenocarcinoma at chr8p23.1 affects enhancer activity and implicates multiple gene targets. Hum Mol Genet 2022; 31:3975-3986. [PMID: 35766871 DOI: 10.1093/hmg/ddac141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 06/09/2022] [Accepted: 06/16/2022] [Indexed: 11/12/2022] Open
Abstract
Nineteen genetic susceptibility loci for esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) have been identified through genome-wide association studies (GWAS). Clinical translation of such discoveries, however, has been hindered by the slow pace of discovery of functional/causal variants and gene targets at these loci. We previously developed a systematic informatics pipeline to prioritize candidate functional variants using functional potential scores, applied the pipeline to select high-scoring BE/EAC risk loci, and validated a functional variant at chr19p13.11 (rs10423674). Here, we selected two additional prioritized loci for experimental interrogation: chr3p13/rs1522552 and chr8p23.1/rs55896564. Candidate enhancer regions encompassing these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two regions tested exhibited allele-specific enhancer activity - 8p23.1/rs55896564. CRISPR-mediated deletion of the putative enhancer in EAC cell lines correlated with reduced expression of three candidate gene targets: B lymphocyte kinase (BLK), nei like DNA glycosylase 2 (NEIL2), and cathepsin B (CTSB). Expression quantitative trait locus (eQTL) mapping in normal esophagus and stomach revealed strong associations between the BE/EAC risk allele at rs55896564 (G) and lower expression of CTSB, a protease gene implicated in epithelial wound repair. These results further support the utility of functional potential scores for GWAS variant prioritization, and provide the first experimental evidence of a functional variant and risk enhancer at the 8p23.1 GWAS locus. Identification of CTSB, BLK, and NEIL2 as candidate gene targets suggests that altered expression of these genes may underlie the genetic risk association at 8p23.1 with BE/EAC.
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Affiliation(s)
- Mourad Wagdy Ali
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Jianhong Chen
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Xiaoyu Wang
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - James Y Dai
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, USA
| | - Graham Casey
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Matthew F Buas
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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17
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Xin J, Jiang X, Ben S, Yuan Q, Su L, Zhang Z, Christiani DC, Du M, Wang M. Association between circulating vitamin E and ten common cancers: evidence from large-scale Mendelian randomization analysis and a longitudinal cohort study. BMC Med 2022; 20:168. [PMID: 35538486 PMCID: PMC9092790 DOI: 10.1186/s12916-022-02366-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 04/05/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The association between vitamin E and cancer risk has been widely investigated by observational studies, but the findings remain inconclusive. Here, we aimed to evaluate the causal effect of circulating vitamin E on the risk of ten common cancers, including bladder, breast, colorectal, esophagus, lung, oral and pharynx, ovarian, pancreatic, prostate, and kidney cancer. METHODS A Mendelian randomization (MR) analytic framework was applied to data from a cancer-specific genome-wide association study (GWAS) comprising a total of 297,699 cancer cases and 304,736 controls of European ancestry. Three genetic instrumental variables associated with circulating vitamin E were selected. Summary statistic-based methods of inverse variance weighting (IVW) and likelihood-based approach, as well as the individual genotyping-based method of genetic risk score (GRS) were used. Multivariable IVW analysis was further performed to control for potential confounding effects. Furthermore, the UK Biobank cohort was used as external validation, supporting 355,543 European participants (incident cases ranged from 437 for ovarian cancer to 4882 for prostate cancer) for GRS-based estimation of circulating vitamin E, accompanied by a one-sample MR analysis of dietary vitamin E intake underlying the time-to-event analytic framework. RESULTS Specific to cancer GWAS, we found that circulating vitamin E was significantly associated with increased bladder cancer risk (odds ratios [OR]IVW = 6.23, PIVW = 3.05×10-3) but decreased breast cancer risk (ORIVW = 0.68, PIVW = 8.19×10-3); however, the significance of breast cancer was dampened (Pmultivariable IVW > 0.05) in the subsequent multivariable MR analysis. In the validation stage of the UK Biobank cohort, we did not replicate convincing causal effects of genetically predicted circulating vitamin E concentrations and dietary vitamin E intake on the risk of ten cancers. CONCLUSIONS This large-scale population study upon data from cancer-specific GWAS and a longitudinal biobank cohort indicates plausible non-causal associations between circulating vitamin E and ten common cancers in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.
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Affiliation(s)
- Junyi Xin
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.,Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China
| | - Xia Jiang
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Shuai Ben
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China
| | - Qianyu Yuan
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Li Su
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China
| | - David C Christiani
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Mulong Du
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China. .,Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.
| | - Meilin Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. .,Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China. .,The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
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18
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Mushtaq S. The Immunogenetics of Non-melanoma Skin Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:397-409. [PMID: 35286705 DOI: 10.1007/978-3-030-92616-8_16] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Non-melanoma skin cancer (NMSC) is the most common malignancy seen in Caucasians and includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The incidence of NMSC is showing an increasing trend which is attributed to the increased use of sunbeds, recreational sun exposure, aging population, and partly to improved screening and reporting. Ultraviolet (UV) radiation plays the most crucial role in the pathogenesis of both BCC and SCC by inducing DNA damage and mutagenic photoproducts. Other risk factors are fair skin, old age, genetic predisposition, immunosuppression, ionizing radiation, organic chemicals, and HPV infection. The role of genomic instability, genetic mutations/aberrations, and host immunity has been fairly illustrated in several studies. This chapter aims to discuss these aspects of NMSC in detail.
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Affiliation(s)
- Sabha Mushtaq
- Department of Dermatology, Venereology, and Leprology, Government Medical College & Associated Hospitals, University of Jammu, Jammu, J&K, 180001, India.
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19
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Jung JO, Wirsik NM, Nienhüser H, Peters L, Müller-Stich BP, Hess T, Schüller V, Schumacher J, Schmidt T. Clinical Relevance of Gastroesophageal Cancer Associated SNPs for Oncologic Outcome After Curative Surgery. Ann Surg Oncol 2022; 29:1453-1462. [PMID: 34529172 PMCID: PMC8724221 DOI: 10.1245/s10434-021-10771-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/18/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Gastric and esophageal cancers are malignant diseases with rising importance in Western countries. To improve oncologic outcome after surgery, it is essential to understand the relevance of germline mutations. The aim of the study was to identify and distinguish clinically relevant single-nucleotide polymorphisms (SNPs). PATIENTS AND METHODS In total, 190 patients with curative oncological resections of gastric and distal esophageal adenocarcinomas at Heidelberg University Hospital were eligible for this study. Outcome differences were determined for each SNP by analysis of clinical variables, survival, and mRNA expression levels. RESULTS Significant survival differences were found on univariate analysis for usual prognostic variables (such as pTNM) and for six SNPs. On multivariate survival analysis, the SNPs rs12268840 (intron variant of MGMT, p = 0.045) and rs9972882 (intron variant of STARD3 and eQTL of PGAP3, p = 0.030) were independent and significant survival predictors along with R status and pT/pN category. Group TT of rs12268840 had the highest rate of second primary carcinoma (30.4%, p = 0.0003), lowest expression of MGMT based on cis-eQTL analysis in normal gastroesophageal tissue (p = 1.99 × 10-17), and worst oncologic outcome. Group AA of rs9972882 had the highest rate of distant metastases pM1 (42.9%, p = 0.0117), highest expression of PGAP3 (p = 1.29 × 10-15), and worst oncologic outcome. CONCLUSIONS Two intron variant SNPs of MGMT and STARD3 were identified that were significant survival predictors and may influence tumor biology. The data indicate that DNA methylation (MGMT) and malfunction of GPI anchoring (PGAP3) are distinct mechanisms that are relevant for tumor progression and relapse.
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Affiliation(s)
- Jin-On Jung
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
- Present address: Department of General, Visceral and Transplantation Surgery, University Clinic Cologne, Cologne, Germany.
| | - Naita Maren Wirsik
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
- Present address: Department of General, Visceral and Transplantation Surgery, University Clinic Cologne, Cologne, Germany
| | - Henrik Nienhüser
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Leila Peters
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Beat Peter Müller-Stich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Timo Hess
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Institute of Human Genetics, University of Marburg, Marburg, Germany
| | | | - Johannes Schumacher
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Institute of Human Genetics, University of Marburg, Marburg, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
- Present address: Department of General, Visceral and Transplantation Surgery, University Clinic Cologne, Cologne, Germany.
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20
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Wu Y, Xin J, Loehrer EA, Jiang X, Yuan Q, Christiani DC, Shi H, Liu L, Li S, Wang M, Chu H, Du M, Zhang Z. High-density lipoprotein, low-density lipoprotein and triglyceride levels and upper gastrointestinal cancers risk: a trans-ancestry Mendelian randomization study. Eur J Clin Nutr 2022; 76:995-1002. [DOI: 10.1038/s41430-022-01078-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 12/18/2021] [Accepted: 01/12/2022] [Indexed: 01/02/2023]
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21
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ten Kate CA, de Klein A, de Graaf BM, Doukas M, Koivusalo A, Pakarinen MP, van der Helm R, Brands T, IJsselstijn H, van Bever Y, Wijnen RM, Spaander MC, Brosens E. Intrinsic Cellular Susceptibility to Barrett's Esophagus in Adults Born with Esophageal Atresia. Cancers (Basel) 2022; 14:cancers14030513. [PMID: 35158780 PMCID: PMC8833471 DOI: 10.3390/cancers14030513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/01/2022] [Accepted: 01/10/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary We investigated the increased prevalence of Barrett’s esophagus in adults with esophageal atresia. A higher polygenic risk score and disturbances in inflammatory, stress response and oncological pathways upon acid exposure suggest a genetic susceptibility and increased induction of inflammatory processes. Although further research is required to explore this hypothesis, this could be a first-step into selecting patients that are more at risk to develop Barrett’s esophagus and/or esophageal carcinoma. Currently, an endoscopic screening and surveillance program is in practice in our institution for patients born with esophageal atresia, to early detect (pre)malignant lesions. Since recurrent endoscopies can be a burden for the patient, selecting patients by for example genetic susceptibility would allow to only include those at risk in future practice. Abstract The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances.
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Affiliation(s)
- Chantal A. ten Kate
- Department of Pediatric Surgery and Intensive Care Children, Erasmus MC-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (C.A.t.K.); (H.I.); (R.M.H.W.)
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, 3000 CA Rotterdam, The Netherlands;
- Department of Clinical Genetics, Erasmus MC Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (A.d.K.); (B.M.d.G.); (R.v.d.H.); (T.B.); (Y.v.B.)
| | - Annelies de Klein
- Department of Clinical Genetics, Erasmus MC Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (A.d.K.); (B.M.d.G.); (R.v.d.H.); (T.B.); (Y.v.B.)
| | - Bianca M. de Graaf
- Department of Clinical Genetics, Erasmus MC Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (A.d.K.); (B.M.d.G.); (R.v.d.H.); (T.B.); (Y.v.B.)
| | - Michail Doukas
- Department of Pathology, Erasmus MC, 3000 CA Rotterdam, The Netherlands;
| | - Antti Koivusalo
- Department of Pediatric Surgery, University of Helsinki, Children’s Hospital, 281, 000290 Helsinki, Finland; (A.K.); (M.P.P.)
| | - Mikko P. Pakarinen
- Department of Pediatric Surgery, University of Helsinki, Children’s Hospital, 281, 000290 Helsinki, Finland; (A.K.); (M.P.P.)
| | - Robert van der Helm
- Department of Clinical Genetics, Erasmus MC Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (A.d.K.); (B.M.d.G.); (R.v.d.H.); (T.B.); (Y.v.B.)
| | - Tom Brands
- Department of Clinical Genetics, Erasmus MC Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (A.d.K.); (B.M.d.G.); (R.v.d.H.); (T.B.); (Y.v.B.)
| | - Hanneke IJsselstijn
- Department of Pediatric Surgery and Intensive Care Children, Erasmus MC-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (C.A.t.K.); (H.I.); (R.M.H.W.)
| | - Yolande van Bever
- Department of Clinical Genetics, Erasmus MC Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (A.d.K.); (B.M.d.G.); (R.v.d.H.); (T.B.); (Y.v.B.)
| | - René M.H. Wijnen
- Department of Pediatric Surgery and Intensive Care Children, Erasmus MC-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (C.A.t.K.); (H.I.); (R.M.H.W.)
| | - Manon C.W. Spaander
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, 3000 CA Rotterdam, The Netherlands;
| | - Erwin Brosens
- Department of Clinical Genetics, Erasmus MC Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (A.d.K.); (B.M.d.G.); (R.v.d.H.); (T.B.); (Y.v.B.)
- Correspondence: ; Tel.: +31-10-70-37643
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22
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Mittal SK, Abdo J, Adrien MP, Bayu BA, Kline JR, Sullivan MM, Agrawal DK. Current state of prognostication, therapy and prospective innovations for Barrett's-related esophageal adenocarcinoma: a literature review. J Gastrointest Oncol 2021; 12:1197-1214. [PMID: 34532080 DOI: 10.21037/jgo-21-117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/30/2021] [Indexed: 12/11/2022] Open
Abstract
Objective Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), which has one of the lowest 5-year survival rates in oncology. The reasons for poor survival are twofold: the large majority of diagnoses are in advanced stages (~80%) and limited treatment options, with a deficit of biology-guided therapies. As a rapidly growing public health concern with poor prognosis, research into the molecular progression for BE and novel therapeutics for EAC currently has high clinical utility. Review of the literature reveals that innovative analysis of metaplastic progression from BE to EAC at a molecular level can shed light on the underlying transformative probabilities of BE into malignant pathologies and may impact current of future therapeutic modalities for management of these diseases. Background EAC is the fastest increasing cancer in the United States with a 600% increase over the past 25 years. This cancer arises from dysplastic tissue of BE, a complication of gastroesophageal reflux disease (GERD). Chronic acid and bile reflux in the distal esophagus initiates a metaplastic conversion of normal squamous epithelium to premalignant intestinalized columnar epithelium. Patients with BE have a 125-fold higher risk of cancer compared to the general population. Methods We critically reviewed the current status of BE monitoring, and subsequent therapeutic strategies being used in patients who have progressed to cancer. Also, new diagnostic tools and therapeutic candidates for BE-related EAC are discussed. Highly-targeted searches of databases containing recent original peer-reviewed papers were utilized for this review. Conclusions Novel and well-described biomarkers analyzed in the patient's diseased tissue will provide for more powerful diagnostics, but also possess the potential to develop strategies for personalized management and identify targets for intervention to either cease disease progression or treat BE and/or EAC. Since millions of Americans develop BE without progressing to cancer, there is a critical need to identify the small percentage of Barrett's patients who possess hallmarks of disease progression or carcinogenesis with novel screening techniques. Incorporation of such tools into standard screening protocols for BE surveillance and/or therapy would be critical to detect malignant transformations before clinically obvious cancer ever develops.
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Affiliation(s)
- Sumeet K Mittal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Dignity Health, Phoenix, AZ, USA
| | - Joe Abdo
- Stella Diagnostics, Inc., Salt Lake City, UT, USA
| | - Malika P Adrien
- Department of Biochemistry, Georgetown University Medical Center, Washington, DC, USA
| | - Binyam A Bayu
- Department of Biochemistry, Georgetown University Medical Center, Washington, DC, USA
| | - Jay R Kline
- Department of Biochemistry, Georgetown University Medical Center, Washington, DC, USA
| | - Molly M Sullivan
- Department of Biochemistry, Georgetown University Medical Center, Washington, DC, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, CA, USA
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23
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Chen J, Ali MW, Yan L, Dighe SG, Dai JY, Vaughan TL, Casey G, Buas MF. Prioritization and functional analysis of GWAS risk loci for Barrett's esophagus and esophageal adenocarcinoma. Hum Mol Genet 2021; 31:410-422. [PMID: 34505128 DOI: 10.1093/hmg/ddab259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/17/2021] [Accepted: 08/30/2021] [Indexed: 01/03/2023] Open
Abstract
Genome-wide association studies (GWAS) have identified ~ 20 genetic susceptibility loci for esophageal adenocarcinoma (EAC), and its precursor, Barrett's esophagus (BE). Despite such advances, functional/causal variants and gene targets at these loci remain undefined, hindering clinical translation. A key challenge is that most causal variants map to non-coding regulatory regions such as enhancers, and typically, numerous potential candidate variants at GWAS loci require testing. We developed a systematic informatics pipeline for prioritizing candidate functional variants via integrative functional potential scores consolidated from multi-omics annotations, and used this pipeline to identify two high-scoring variants for experimental interrogation: chr9q22.32/rs11789015 and chr19p13.11/rs10423674. Minimal candidate enhancer regions spanning these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two variants tested (rs10423674) exhibited allele-specific enhancer activity. CRISPR-mediated deletion of the putative enhancer region in EAC cell lines correlated with reduced expression of two genes-CREB-regulated transcription coactivator 1 (CRTC1) and Cartilage oligomeric matrix protein (COMP); expression of five other genes remained unchanged (CRLF1, KLHL26, TMEM59L, UBA52, RFXANK). Expression quantitative trait locus (eQTL) mapping indicated that rs10423674 genotype correlated with CRTC1 and COMP expression in normal esophagus. This study represents the first experimental effort to bridge GWAS associations to biology in BE/EAC, and supports the utility of functional potential scores to guide variant prioritization. Our findings reveal a functional variant and candidate risk enhancer at chr19p13.11, and implicate CRTC1 and COMP as putative gene targets, suggesting that altered expression of these genes may underlie the BE/EAC risk association.
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Affiliation(s)
- Jianhong Chen
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263 USA
| | - Mourad Wagdy Ali
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903 USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263 USA
| | - Shruti G Dighe
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263 USA
| | - James Y Dai
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 USA
| | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 USA.,Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, 98195 USA
| | - Graham Casey
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22903 USA
| | - Matthew F Buas
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263 USA
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24
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Ye B, Fan D, Xiong W, Li M, Yuan J, Jiang Q, Zhao Y, Lin J, Liu J, Lv Y, Wang X, Li Z, Su J, Qiao Y. Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis. Nat Commun 2021; 12:4457. [PMID: 34294701 PMCID: PMC8298514 DOI: 10.1038/s41467-021-24813-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 07/01/2021] [Indexed: 01/27/2023] Open
Abstract
The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment.
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Affiliation(s)
- Bo Ye
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Dandan Fan
- School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Weiwei Xiong
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Min Li
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Jian Yuan
- School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Qi Jiang
- School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yuting Zhao
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
- Guangzhou University & Zhongshan People's Hospital Joint Biomedical Institute, Guangzhou, China
| | - Jianxiang Lin
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Jie Liu
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Yilv Lv
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Xiongjun Wang
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China
| | - Zhigang Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
| | - Jianzhong Su
- School of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China.
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
| | - Yunbo Qiao
- Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China.
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25
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Global burden and epidemiology of Barrett oesophagus and oesophageal cancer. Nat Rev Gastroenterol Hepatol 2021; 18:432-443. [PMID: 33603224 DOI: 10.1038/s41575-021-00419-3] [Citation(s) in RCA: 189] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/14/2021] [Indexed: 02/07/2023]
Abstract
Oesophageal cancer is a global health problem; in 2018 there were more than 572,000 people newly diagnosed with oesophageal cancer worldwide. There are two main histological subtypes of oesophageal cancer, oesophageal adenocarcinoma (EAC) and oesophageal squamous cell carcinoma (ESCC), and there has been a dramatic shift in its epidemiology. While the incidence of EAC and its precursor lesion, Barrett oesophagus, has increased in Western populations over the past four decades, the incidence of ESCC has declined in most parts of the world over the same period. ESCC still accounts for the vast majority of all oesophageal cancer cases diagnosed worldwide each year. Prognosis for patients with oesophageal cancer is strongly related to stage at diagnosis. As most patients are diagnosed with late-stage disease, overall 5-year survival for oesophageal cancer remains <20%. Knowledge of epidemiology and risk factors for oesophageal cancer is essential for public health and clinical decisions about risk stratification, screening and prevention. The goal of this Review is to establish the current epidemiology of oesophageal cancer, with a particular focus on the Western world and the increasing incidence of EAC and Barrett oesophagus.
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26
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De A, Zhou J, Liu P, Huang M, Gunewardena S, Mathur SC, Christenson LK, Sharma M, Zhang Q, Bansal A. Forkhead box F1 induces columnar phenotype and epithelial-to-mesenchymal transition in esophageal squamous cells to initiate Barrett's like metaplasia. J Transl Med 2021; 101:745-759. [PMID: 33495575 PMCID: PMC9296259 DOI: 10.1038/s41374-021-00534-4] [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: 04/24/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 11/08/2022] Open
Abstract
Multiple genome-wide association studies (GWAS) have linked Forkhead Box F1 (FOXF1) to Barrett's esophagus (BE). Understanding whether FOXF1 is involved in initiation of Barrett's metaplasia could allow FOXF1 to be used for risk stratification and for therapy. Two-dimensional cell cultures and three-dimensional organoid cultures and well-annotated human biopsies were used to determine the role of FOXF1 in BE pathogenesis. Multiple established esophageal squamous and BE cell lines were tested in gain- and loss-of-function studies. Initiation of a BE-like metaplastic change was evaluated by measuring characteristic cytokeratins and global gene expression profiling and by culturing organoids. Epithelial-mesenchymal transition (EMT) was evaluated by immunostaining for E-cadherin, vimentin and Snail, and by cell motility assay. Columnar esophageal epithelium of BE patients exhibited higher expression of FOXF1 compared to normal squamous esophageal epithelium of GERD patients (P < 0.001). Acidic bile salts induced nuclear FOXF1 in esophageal squamous cells. FOXF1 overexpression in normal esophageal squamous cells: (a) increased columnar cytokeratins and decreased squamous cytokeratins, (b) converted squamous organoids to glandular organoids, and (c) switched global gene profiles to resemble that of human BE epithelium (P = 2.1685e - 06 for upregulated genes and P = 8.3378e - 09 for downregulated genes). FOXF1 inhibition in BE cell lines led to loss of BE differentiation markers, CK7, and mucin 2. Also, FOXF1 induced EMT and promoted cell motility in normal esophageal squamous epithelial cells. FOXF1-induced genes mapped to pathways such as Cancer, Cellular Assembly and Organization, DNA Replication, Recombination, and Repair. In conclusion, FOXF1 promotes a BE-like columnar phenotype and cell motility in esophageal squamous epithelial cells, which may have a critical role in BE development. FOXF1 should be studied further as a biomarker for BE and as a target for BE treatment.
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Affiliation(s)
- Alok De
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Jianping Zhou
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Pi Liu
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, 75246, USA
| | - Manling Huang
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, 75246, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Sharad C Mathur
- Department of Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Kansas City, MO, USA
- The University of Kansas Medical Center, Kansas City, KS, USA
| | - Lane K Christenson
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Mukut Sharma
- Midwest Veterans' Biomedical Research Foundation (MVBRF), Kansas City, MO, USA
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, USA
| | - Qiuyang Zhang
- Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX, 75246, USA.
| | - Ajay Bansal
- Division of Gastroenterology and Hepatology, The University of Kansas Medical Center, Kansas City, KS, USA.
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO, USA.
- The University of Kansas Cancer Center, Kansas City, KS, USA.
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27
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Elliott JA, Reynolds JV. Visceral Obesity, Metabolic Syndrome, and Esophageal Adenocarcinoma. Front Oncol 2021; 11:627270. [PMID: 33777773 PMCID: PMC7994523 DOI: 10.3389/fonc.2021.627270] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/19/2021] [Indexed: 12/16/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) represents an exemplar of obesity-associated carcinogenesis, with a progressive increase in EAC risk with increased body mass index. In this context, there is increased focus on visceral adipose tissue and associated metabolic dysfunction, including hypertension, diabetes mellitus and hyperlipidemia, or combinations of these in the metabolic syndrome. Visceral obesity (VO) may promote EAC via both directly impacting on gastro-esophageal reflux disease and Barrett's esophagus, as well as via reflux-independent effects, involving adipokines, growth factors, insulin resistance, and the microbiome. In this review these pathways are explored, including the impact of VO on the tumor microenvironment, and on cancer outcomes. The current evidence-based literature regarding the role of dietary, lifestyle, pharmacologic and surgical interventions to modulate the risk of EAC is explored.
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Affiliation(s)
- Jessie A Elliott
- Trinity St. James's Cancer Institute, Trinity College Dublin and St. James's Hospital, Dublin, Ireland
| | - John V Reynolds
- Trinity St. James's Cancer Institute, Trinity College Dublin and St. James's Hospital, Dublin, Ireland
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28
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Abstract
Barrett’s oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated adenomatous polyposis. Patients with a genetically confirmed diagnosis of familial adenomatous polyposis (FAP) or MAP were selected and upper gastrointestinal (GI) endoscopy reports, pathology reports of upper GI biopsies were reviewed to determine the prevalence of BE in these patients. Histologically confirmed BE was found in 7 (9.7%) of 72 patients with MAP. The mean age of diagnosis was 60.2 years (range 54.1–72.4 years). Two patients initially diagnosed with low grade dysplasia showed fast progression into high grade dysplasia and esophageal cancer, respectively. Only 4 (1.4%) of 365 patients with FAP were found to have pathologically confirmed BE. The prevalence of BE in patients with MAP is much higher than reported in the general population. We recommend that upper GI surveillance of patients with MAP should not only focus on the detection of gastric and duodenal adenomas but also on the presence of BE.
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29
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Wu Y, Murray GK, Byrne EM, Sidorenko J, Visscher PM, Wray NR. GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression. Nat Commun 2021; 12:1146. [PMID: 33608531 PMCID: PMC7895976 DOI: 10.1038/s41467-021-21280-7] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 01/06/2021] [Indexed: 01/31/2023] Open
Abstract
Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genes MUC1, MUC6, FUT2, PSCA, ABO, CDX2, GAST and CCKBR. There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
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Affiliation(s)
- Yeda Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
| | - Graham K Murray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Enda M Byrne
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Julia Sidorenko
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Peter M Visscher
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Naomi R Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
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30
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Landini A, Yu S, Gnecchi‐Ruscone GA, Abondio P, Ojeda‐Granados C, Sarno S, De Fanti S, Gentilini D, Di Blasio AM, Jin H, Nguyen TT, Romeo G, Prata C, Bortolini E, Luiselli D, Pettener D, Sazzini M. Genomic adaptations to cereal-based diets contribute to mitigate metabolic risk in some human populations of East Asian ancestry. Evol Appl 2021; 14:297-313. [PMID: 33664777 PMCID: PMC7896717 DOI: 10.1111/eva.13090] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 07/20/2020] [Accepted: 08/04/2020] [Indexed: 12/21/2022] Open
Abstract
Adoption of diets based on some cereals, especially on rice, signified an iconic change in nutritional habits for many Asian populations and a relevant challenge for their capability to maintain glucose homeostasis. Indeed, rice shows the highest carbohydrates content and glycemic index among the domesticated cereals and its usual ingestion represents a potential risk factor for developing insulin resistance and related metabolic diseases. Nevertheless, type 2 diabetes and obesity epidemiological patterns differ among Asian populations that rely on rice as a staple food, with higher diabetes prevalence and increased levels of central adiposity observed in people of South Asian ancestry rather than in East Asians. This may be at least partly due to the fact that populations from East Asian regions where wild rice or other cereals such as millet have been already consumed before their cultivation and/or were early domesticated have relied on these nutritional resources for a period long enough to have possibly evolved biological adaptations that counteract their detrimental side effects. To test such a hypothesis, we compared adaptive evolution of these populations with that of control groups from regions where the adoption of cereal-based diets occurred many thousand years later and which were identified from a genome-wide dataset including 2,379 individuals from 124 East Asian and South Asian populations. This revealed selective sweeps and polygenic adaptive mechanisms affecting functional pathways involved in fatty acids metabolism, cholesterol/triglycerides biosynthesis from carbohydrates, regulation of glucose homeostasis, and production of retinoic acid in Chinese Han and Tujia ethnic groups, as well as in people of Korean and Japanese ancestry. Accordingly, long-standing rice- and/or millet-based diets have possibly contributed to trigger the evolution of such biological adaptations, which might represent one of the factors that play a role in mitigating the metabolic risk of these East Asian populations.
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Affiliation(s)
- Arianna Landini
- Laboratory of Molecular Anthropology & Centre for Genome BiologyDepartment of Biological, Geological and Environmental SciencesUniversity of BolognaBolognaItaly
- Centre for Global Health ResearchUsher Institute of Population Health Sciences and InformaticsUniversity of EdinburghEdinburghUK
| | - Shaobo Yu
- Laboratory of Molecular Anthropology & Centre for Genome BiologyDepartment of Biological, Geological and Environmental SciencesUniversity of BolognaBolognaItaly
| | | | - Paolo Abondio
- Laboratory of Molecular Anthropology & Centre for Genome BiologyDepartment of Biological, Geological and Environmental SciencesUniversity of BolognaBolognaItaly
| | - Claudia Ojeda‐Granados
- Laboratory of Molecular Anthropology & Centre for Genome BiologyDepartment of Biological, Geological and Environmental SciencesUniversity of BolognaBolognaItaly
- Department of Molecular Biology in MedicineCivil Hospital of Guadalajara “Fray Antonio Alcalde” and Health Sciences CenterUniversity of GuadalajaraGuadalajaraMexico
| | - Stefania Sarno
- Laboratory of Molecular Anthropology & Centre for Genome BiologyDepartment of Biological, Geological and Environmental SciencesUniversity of BolognaBolognaItaly
| | - Sara De Fanti
- Interdepartmental Centre Alma Mater Research Institute on Global Challenges and Climate ChangeUniversity of BolognaBolognaItaly
| | - Davide Gentilini
- Department of Brain and Behavioral SciencesUniversity of PaviaPaviaItaly
- Italian Auxologic Institute IRCCSCusano Milanino, MilanItaly
| | | | - Hanjun Jin
- Department of Biological SciencesCollege of Natural ScienceDankook UniversityCheonanSouth Korea
| | | | - Giovanni Romeo
- Medical Genetics UnitS. Orsola HospitalUniversity of BolognaBolognaItaly
- European School of Genetic MedicineItaly
| | - Cecilia Prata
- Department of Pharmacy and BiotechnologyUniversity of BolognaBolognaItaly
| | | | - Donata Luiselli
- Department of Cultural HeritageUniversity of BolognaRavennaItaly
| | - Davide Pettener
- Laboratory of Molecular Anthropology & Centre for Genome BiologyDepartment of Biological, Geological and Environmental SciencesUniversity of BolognaBolognaItaly
| | - Marco Sazzini
- Laboratory of Molecular Anthropology & Centre for Genome BiologyDepartment of Biological, Geological and Environmental SciencesUniversity of BolognaBolognaItaly
- Interdepartmental Centre Alma Mater Research Institute on Global Challenges and Climate ChangeUniversity of BolognaBolognaItaly
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31
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Dighe SG, Chen J, Yan L, He Q, Gharahkhani P, Onstad L, Levine DM, Palles C, Ye W, Gammon MD, Iyer PG, Anderson LA, Liu G, Wu AH, Dai JY, Chow WH, Risch HA, Lagergren J, Shaheen NJ, Bernstein L, Corley DA, Prenen H, deCaestecker J, MacDonald D, Moayyedi P, Barr H, Love SB, Chegwidden L, Attwood S, Watson P, Harrison R, Ott K, Moebus S, Venerito M, Lang H, Mayershofer R, Knapp M, Veits L, Gerges C, Weismüller J, Gockel I, Vashist Y, Nöthen MM, Izbicki JR, Manner H, Neuhaus H, Rösch T, Böhmer AC, Hölscher AH, Anders M, Pech O, Schumacher B, Schmidt C, Schmidt T, Noder T, Lorenz D, Vieth M, May A, Hess T, Kreuser N, Becker J, Ell C, Ambrosone CB, Moysich KB, MacGregor S, Tomlinson I, Whiteman DC, Jankowski J, Schumacher J, Vaughan TL, Madeleine MM, Hardie LJ, Buas MF. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis 2020; 42:369-377. [PMID: 33300568 PMCID: PMC8052954 DOI: 10.1093/carcin/bgaa132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/21/2020] [Accepted: 12/08/2020] [Indexed: 12/21/2022] Open
Abstract
Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.
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Affiliation(s)
- Shruti G Dighe
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Jianhong Chen
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Qianchuan He
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Lynn Onstad
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - David M Levine
- Department of Biostatistics, University of Washington, School of Public Health, Seattle, WA, USA
| | - Claire Palles
- Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Weimin Ye
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Marilie D Gammon
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Lesley A Anderson
- Department of Epidemiology and Public Health, Queen’s University of Belfast, Royal Group of Hospitals, Belfast, UK
| | - Geoffrey Liu
- Department of Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada
| | - Anna H Wu
- Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - James Y Dai
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Wong-Ho Chow
- Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, USA
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden,Department of Surgery, School of Cancer and Pharmaceutical Sciences, King’s College London
| | - Nicholas J Shaheen
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Leslie Bernstein
- Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA,Gastroenterology, San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, USA
| | - Hans Prenen
- Oncology Department, University Hospital Antwerp, Edegem, Belgium
| | - John deCaestecker
- Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK
| | - David MacDonald
- Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Paul Moayyedi
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Hugh Barr
- Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK
| | - Sharon B Love
- Centre for Statistics in Medicine, University of Oxford, Oxford, UK; MRC Clinical Trials Unit at University College London, London, UK
| | - Laura Chegwidden
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
| | - Stephen Attwood
- Department of General Surgery, North Tyneside General Hospital, North Shields, UK
| | - Peter Watson
- Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK
| | - Rebecca Harrison
- Department of Pathology, Leicester Royal Infirmary, Leicester, UK
| | - Katja Ott
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany,Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Susanne Moebus
- Biometry and Epidemiology, Institute for Urban Public Health, University Hospitals, University of Duisburg-Essen, Essen, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | | | - Michael Knapp
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
| | - Lothar Veits
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Christian Gerges
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany
| | | | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Yogesh Vashist
- Department of Surgery, Asklepios Harzklinik Goslar, Goslar, Germany
| | - Markus M Nöthen
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hendrik Manner
- Department of Internal Medicine II, Frankfurt Hoechst Hospital, Frankfurt, Germany
| | - Horst Neuhaus
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Thomas Rösch
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Anne C Böhmer
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Arnulf H Hölscher
- Clinic for General, Visceral and Trauma Surgery, Department of Surgery, Contilia Center for Esophageal Diseases. Elisabeth Hospital, Essen, Germany
| | - Mario Anders
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany,Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany
| | - Oliver Pech
- Department of Gastroenterology and Interventional Endoscopy, St. John of God Hospital, Regensburg, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany,Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | - Claudia Schmidt
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Tania Noder
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Dietmar Lorenz
- Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Andrea May
- Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Klinik, Wiesbaden, Germany
| | - Timo Hess
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Jessica Becker
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Christian Ell
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Christine B Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kirsten B Moysich
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Ian Tomlinson
- Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - David C Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Janusz Jankowski
- Division of Medicine Kings Mill Hospital, Sherwood Hospitals NHS Trust, Nottinghamshire, UK,Comprehensive Clinical Trials Unit, University College London, London, UK,Dean’s Office, College of Medicine and Health Sciences (CMHS), AL Ain, UAE
| | | | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA, USA
| | - Margaret M Madeleine
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA, USA
| | - Laura J Hardie
- Department of Epidemiology, University of Leeds, Leeds, UK,Correspondence may also be addressed to Laura J. Hardie. Tel: +44(0)113 343 7769;
| | - Matthew F Buas
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA,To whom correspondence should be addressed. Tel: +1 716-845-4754;
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Dong J, Maj C, Tsavachidis S, Ostrom QT, Gharahkhani P, Anderson LA, Wu AH, Ye W, Bernstein L, Borisov O, Schröder J, Chow WH, Gammon MD, Liu G, Caldas C, Pharoah PD, Risch HA, May A, Gerges C, Anders M, Venerito M, Schmidt T, Izbicki JR, Hölscher AH, Schumacher B, Vashist Y, Neuhaus H, Rösch T, Knapp M, Krawitz P, Böhmer A, Iyer PG, Reid BJ, Lagergren J, Shaheen NJ, Corley DA, Gockel I, Fitzgerald RC, Cook MB, Whiteman DC, Vaughan TL, Schumacher J, Thrift AP. Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma. Gastroenterology 2020; 159:2065-2076.e1. [PMID: 32918910 PMCID: PMC9057456 DOI: 10.1053/j.gastro.2020.08.052] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 08/04/2020] [Accepted: 08/24/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
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Affiliation(s)
- Jing Dong
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Division of Hematology and Oncology, Department of Medicine, Cancer Center, and Genomic Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Carlo Maj
- Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany
| | - Spiridon Tsavachidis
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Quinn T Ostrom
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Lesley A Anderson
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland & Aberdeen Center for Health Data Science, University of Aberdeen, Scotland
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Leslie Bernstein
- Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California
| | - Oleg Borisov
- Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany
| | - Julia Schröder
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Wong-Ho Chow
- Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas
| | - Marilie D Gammon
- Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina
| | - Geoffrey Liu
- Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada
| | - Carlos Caldas
- Cancer Research UK, Cambridge Institute, Cambridge, UK
| | - Paul D Pharoah
- Department of Oncology, University of Cambridge, Cambridge, UK; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
| | - Andrea May
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Christian Gerges
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Mario Anders
- Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
| | - Arnulf H Hölscher
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | - Yogesh Vashist
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
| | - Horst Neuhaus
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Thomas Rösch
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Knapp
- Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Peter Krawitz
- Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany
| | - Anne Böhmer
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Brian J Reid
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Nicholas J Shaheen
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, California; San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Rebecca C Fitzgerald
- Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK
| | - Michael B Cook
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland
| | - David C Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | | - Aaron P Thrift
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
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Xie SH, Fang R, Huang M, Dai J, Thrift AP, Anderson LA, Chow WH, Bernstein L, Gammon MD, Risch HA, Shaheen NJ, Reid BJ, Wu AH, Iyer PG, Liu G, Corley DA, Whiteman DC, Caldas C, Pharoah PD, Hardie LJ, Fitzgerald RC, Shen H, Vaughan TL, Lagergren J. Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus. Clin Gastroenterol Hepatol 2020; 18:2701-2709.e3. [PMID: 31756444 PMCID: PMC7580878 DOI: 10.1016/j.cgh.2019.11.030] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/31/2019] [Accepted: 11/10/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett's esophagus (BE). METHODS We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. RESULTS Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. CONCLUSIONS In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.
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Affiliation(s)
- Shao-Hua Xie
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
| | - Rui Fang
- Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Mingtao Huang
- Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Juncheng Dai
- Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Aaron P Thrift
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Lesley A Anderson
- Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom
| | - Wong-Ho Chow
- Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas
| | - Leslie Bernstein
- Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California
| | - Marilie D Gammon
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
| | - Nicholas J Shaheen
- Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Brian J Reid
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Anna H Wu
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Geoffrey Liu
- Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - David C Whiteman
- Cancer Control, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Carlos Caldas
- Cancer Research UK, Cambridge Institute, Cambridge, United Kingdom
| | - Paul D Pharoah
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Laura J Hardie
- Division of Epidemiology, Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom
| | - Rebecca C Fitzgerald
- Medical Research Council Cancer Unit, Hutchison-Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jesper Lagergren
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
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Hull R, Mbele M, Makhafola T, Hicks C, Wang SM, Reis RM, Mehrotra R, Mkhize-Kwitshana Z, Hussain S, Kibiki G, Bates DO, Dlamini Z. A multinational review: Oesophageal cancer in low to middle-income countries. Oncol Lett 2020; 20:42. [PMID: 32802164 PMCID: PMC7412736 DOI: 10.3892/ol.2020.11902] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022] Open
Abstract
Oesophageal cancer (OC) is an aggressive neoplasm that manifests in the gastrointestinal tract and is the result of numerous factors that can contribute to the development of the disease. These may include old age, nutritional deficiencies, oesophageal obstruction and food ingestion difficulties. Environmental factors serve a large role in increasing the risk of developing OC. Two factors that serve an increasing risk of developing OC are the use of tobacco and the consumption of alcohol. Genetic factors also exhibit a large effect on the risk of developing OC, for example, the causative genes in Black Africans differ from other races. OC is 3-4 times more common among men than women. OC has been previously reported in >450 000 individuals worldwide, and its incidence is increasing. The current review compares OC in low to middle-income countries with developed countries. The incidence of OC, particularly squamous cell carcinoma (SCC) is high in low and middle-income countries. In developed countries, the incidence of SCC is low compared with adenocarcinoma. The majority of OC cases are diagnosed in the late stages of the disease, leading to high mortality rates. The current review aimed to discuss factors that contribute to the development of this disease in different geographical areas and genetic mechanisms governing these findings. The current review also aims to discuss the preventative treatment options for the disease, and also discusses the diagnosis and surveillance in five LMICs, including South Africa, China, Tanzania, India and Brazil.
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Affiliation(s)
- Rodney Hull
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
| | - Mzwandile Mbele
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
| | - Tshepiso Makhafola
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
| | - Chindo Hicks
- Louisiana State University, School of Medicine, Department of Genetics, Bioinformatics and Genomics Centre, LA 70112, USA
| | - Shao Ming Wang
- National Cancer Centre, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Rui Manuel Reis
- Molecular Oncology Research Centre, Barretos Cancer Hospital, CEP 14784 400, Sao Paulo, Brazil
| | - Ravi Mehrotra
- Indian Council of Medical Research, 110029 New Delhi, India
| | | | - Showket Hussain
- East African Health Research Commission, East African Community, Quartier Kigobe, 1096 Arusha, United Republic of Tanzania
| | - Gibson Kibiki
- East African Health Research Commission, East African Community, Quartier Kigobe, 1096 Arusha, United Republic of Tanzania
| | - David O. Bates
- University of Nottingham, Queens Medical Centre, Cancer Biology, NG7 2UH Nottingham, UK
| | - Zodwa Dlamini
- South African-Medical Research Council/University of Pretoria Precision, Prevention and Novel Drug Targets for HIV-Associated Cancers Extramural Unit, Cancer Research Institute, University of Pretoria, Faculty of Health Sciences, Pretoria, Gauteng 0028, South Africa
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35
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Maitra I, Date RS, Martin FL. Towards screening Barrett's oesophagus: current guidelines, imaging modalities and future developments. Clin J Gastroenterol 2020; 13:635-649. [PMID: 32495144 PMCID: PMC7519897 DOI: 10.1007/s12328-020-01135-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023]
Abstract
Barrett's oesophagus is the only known precursor to oesophageal adenocarcinoma (OAC). Although guidelines on the screening and surveillance exist in Barrett's oesophagus, the current strategies are inadequate. Oesophagogastroduodenoscopy (OGD) is the gold standard method in screening for Barrett's oesophagus. This invasive method is expensive with associated risks negating its use as a current screening tool for Barrett's oesophagus. This review explores current definitions, epidemiology, biomarkers, surveillance, and screening in Barrett's oesophagus. Imaging modalities applicable to this condition are discussed, in addition to future developments. There is an urgent need for an alternative non-invasive method of screening and/or surveillance which could be highly beneficial towards reducing waiting times, alleviating patient fears and reducing future costs in current healthcare services. Vibrational spectroscopy has been shown to be promising in categorising Barrett's oesophagus through to high-grade dysplasia (HGD) and OAC. These techniques need further validation through multicentre trials.
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Affiliation(s)
- Ishaan Maitra
- School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, PR1 2HE UK
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36
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Boldrin E, Curtarello M, Dallan M, Alfieri R, Realdon S, Fassan M, Saggioro D. Detection of LINE-1 hypomethylation in cfDNA of Esophageal Adenocarcinoma Patients. Int J Mol Sci 2020; 21:1547. [PMID: 32102481 PMCID: PMC7073170 DOI: 10.3390/ijms21041547] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/13/2020] [Accepted: 02/21/2020] [Indexed: 12/12/2022] Open
Abstract
DNA methylation plays an important role in cancer development. Cancer cells exhibit two types of DNA methylation alteration: site-specific hypermethylation at promoter of oncosuppressor genes and global DNA hypomethylation. This study evaluated the methylation patterns of long interspersed nuclear element (LINE-1) sequences which, due to their relative abundance in the genome, are considered a good surrogate indicator of global DNA methylation. LINE-1 methylation status was investigated in the cell-free DNA (cfDNA) of 21 patients, 19 with esophageal adenocarcinoma (EADC) and 2 with Barrett's esophagus (BE). The two BE patients and one EADC patient were also analyzed longitudinally. Methylation status was analyzed using restriction enzymes and DNA amplification. This methodology was chosen to avoid bisulfite conversion, which we considered inadequate for cfDNA analysis. Indeed, cfDNA is characterized by poor quality and low concentration, and bisulfite conversion might worsen these conditions. Results showed that hypomethylated LINE-1 sequences are present in EADC cfDNA. Furthermore, longitudinal studies in BE suggested a correlation between methylation status of LINE-1 sequences in cfDNA and progression to EADC. In conclusion, our study indicated the feasibility of our methodological approach to detect hypomethylation events in cfDNA from EADC patients, and suggests LINE-1 methylation analysis as a new possible molecular assay to integrate into patient monitoring.
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Affiliation(s)
- Elisa Boldrin
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata 64, 35128 Padova, Italy; (M.C.); (M.D.); (D.S.)
| | - Matteo Curtarello
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata 64, 35128 Padova, Italy; (M.C.); (M.D.); (D.S.)
| | - Marco Dallan
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata 64, 35128 Padova, Italy; (M.C.); (M.D.); (D.S.)
| | - Rita Alfieri
- Oncological Surgery, Veneto Institute of Oncology IOV-IRCCS, via dei Carpani 16, 31033 Castelfranco Veneto, Italy;
| | - Stefano Realdon
- Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata 64, 35128 Padova, Italy;
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology, University of Padova, via Giustiniani 2, 35128 Padova, Italy;
| | - Daniela Saggioro
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata 64, 35128 Padova, Italy; (M.C.); (M.D.); (D.S.)
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Hu P, Huang Y, Gao Y, Yan H, Li X, Zhang J, Wang Y, Zhao Y. Elevated Expression of LYPD3 Is Associated with Lung Adenocarcinoma Carcinogenesis and Poor Prognosis. DNA Cell Biol 2020; 39:522-532. [PMID: 32040344 DOI: 10.1089/dna.2019.5116] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aberrant expression of LYPD3 plays an oncogenic role in several types of cancer. However, the functions of LYPD3 in lung adenocarcinoma (LUAD) remain unclear. Here, we investigated the regulatory function, clinical value, and prognostic significance of LYPD3 in LUAD patients. The gene expression and DNA methylation data of LUAD tumor and paracancerous tissues were obtained from The Cancer Genome Atlas (TCGA) database. The association between LYPD3 expression and clinicopathological variables was analyzed. The results showed that LYPD3 was highly expressed in LUAD tumor compared with paracancerous tissues, which was positively correlated with the race (p = 0.0448), tumor stage (p = 0.0191), and survival status (p < 0.001). Furthermore, the expression of LYPD3 was able to be regulated by the methylation in LYPD3 promoter region, which was positively associated with the overall survival. Furthermore, we explored the related pathways through which LYPD3 affects the pathogenesis and prognosis of LUAD by gene set enrichment analysis, and found that LYPD3 might affect the clinical manifestations of LUAD by regulating the P53 signaling pathway. In the future, we would focus on exploring the molecular mechanism of LYPD3 in the regulation of the occurrence and development of LUAD to provide a research basis for the screening of methylation markers related to the treatment and prognosis.
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Affiliation(s)
- Ping Hu
- Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, P.R. China
| | - Ying Huang
- The Third Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan, P.R. China
| | - Yuanyuan Gao
- The Third Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan, P.R. China
| | - Hui Yan
- The Second Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan, P.R. China
| | - Xiaoge Li
- Department of Paediatrics, Tianjin Jinnan Xiaozhan Hospital, Tianjin, P.R. China
| | - Jiao Zhang
- Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, P.R. China
| | - Yan Wang
- Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, P.R. China
| | - Yanjiao Zhao
- The Third Department of Medicine Oncology, General Hospital of Ningxia Medical University, Yinchuan, P.R. China
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Li G, Song Q, Jiang Y, Cai A, Tang Y, Tang N, Yi D, Zhang R, Wei Z, Liu D, Chen J, Zhang Y, Liu L, Wu Y, Zhang B, Yi D. Cumulative Evidence for Associations between Genetic Variants and Risk of Esophageal Cancer. Cancer Epidemiol Biomarkers Prev 2020; 29:838-849. [PMID: 31969372 DOI: 10.1158/1055-9965.epi-19-1281] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/06/2019] [Accepted: 01/17/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND A large number of studies have been conducted to investigate associations between genetic variants and esophageal cancer risk in the past several decades. However, findings from these studies have been generally inconsistent. We aimed to provide a summary of the current understanding of the genetic architecture of esophageal cancer susceptibility. METHODS We performed a comprehensive field synopsis and meta-analysis to evaluate associations between 95 variants in 70 genes or loci and esophageal cancer risk using data from 304 eligible publications, including 104,904 cases and 159,797 controls, through screening a total of 21,328 citations. We graded levels of cumulative epidemiologic evidence of a significant association with esophageal cancer using the Venice criteria and false-positive report probability tests. We constructed functional annotations for these variants using data from the Encyclopedia of DNA Elements Project and other databases. RESULTS Thirty variants were nominally significantly associated with esophageal cancer risk. Cumulative epidemiologic evidence of a significant association with overall esophageal cancer, esophageal squamous cell carcinoma, or esophageal adenocarcinoma was strong for 13 variants in or near 13 genes (ADH1B, BARX1, CDKN1A, CHEK2, CLPTM1L, CRTC1, CYP1A1, EGF, LTA, MIR34BC, PLCE1, PTEN, and PTGS2). Bioinformatics analysis suggested that these variants and others correlated with them might fall in putative functional regions. CONCLUSIONS Our study summarizes the current literature on the genetic architecture of esophageal cancer susceptibility and identifies several potential polymorphisms that could be involved in esophageal cancer susceptibility. IMPACT These findings provide direction for future studies to identify new genetic factors for esophageal cancer.
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Affiliation(s)
- Gaoming Li
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Qiuyue Song
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Yuxing Jiang
- Medical Department, The 305 Hospital of Chinese People's Liberation Army, Beijing, China
| | - Angsong Cai
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Yong Tang
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Ning Tang
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Dali Yi
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Rui Zhang
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Zeliang Wei
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Dingxin Liu
- Department of Statistics, Chongqing Technology and Business University, Chongqing, China
| | - Jia Chen
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Yanqi Zhang
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Ling Liu
- Department of Health Statistics, Army Medical University, Chongqing, China
| | - Yazhou Wu
- Department of Health Statistics, Army Medical University, Chongqing, China.
| | - Ben Zhang
- Department of Epidemiology and Biostatistics, First Affiliated Hospital, Army Medical University, Chongqing, China.
| | - Dong Yi
- Department of Health Statistics, Army Medical University, Chongqing, China.
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Schröder J, Schüller V, May A, Gerges C, Anders M, Becker J, Hess T, Kreuser N, Thieme R, Ludwig KU, Noder T, Venerito M, Veits L, Schmidt T, Fuchs C, Izbicki JR, Hölscher AH, Dakkak D, Jansen-Winkeln B, Moulla Y, Lyros O, Niebisch S, Mehdorn M, Lang H, Lorenz D, Schumacher B, Mayershofer R, Vashist Y, Ott K, Vieth M, Weismüller J, Mangold E, Nöthen MM, Moebus S, Knapp M, Neuhaus H, Rösch T, Ell C, Gockel I, Schumacher J, Böhmer AC. Identification of loci of functional relevance to Barrett's esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data. PLoS One 2019; 14:e0227072. [PMID: 31891614 PMCID: PMC6938334 DOI: 10.1371/journal.pone.0227072] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/10/2019] [Indexed: 01/29/2023] Open
Abstract
Esophageal adenocarcinoma (EA) and its precancerous condition Barrett's esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10-8) and novel candidate loci (5×10-8 ≤ P ≤ 5×10-5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10-7 and rs1540, Pcombined = 4.16×10-6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.
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Affiliation(s)
- Julia Schröder
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Vitalia Schüller
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Andrea May
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Christian Gerges
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Mario Anders
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
- Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany
| | - Jessica Becker
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Timo Hess
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
- Center for Human Genetics, University Hospital Marburg, Marburg, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Kerstin U. Ludwig
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Tania Noder
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Lothar Veits
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Claudia Fuchs
- Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Jakob R. Izbicki
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
| | - Arnulf H. Hölscher
- Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Dani Dakkak
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | - Boris Jansen-Winkeln
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Yusef Moulla
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Orestis Lyros
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Stefan Niebisch
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Matthias Mehdorn
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Hauke Lang
- Department of General, Visceral, and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Dietmar Lorenz
- Department of General, Visceral, and Thoracic Surgery, Klinikum Darmstadt, Darmstadt, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | | | - Yogesh Vashist
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
- Kantonsspital Aarau, Aarau, Switzerland
| | - Katja Ott
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
- Department of General, Visceral, and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | | | - Elisabeth Mangold
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Markus M. Nöthen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Susanne Moebus
- Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry, and Epidemiology, University of Essen, Essen, Germany
| | - Michael Knapp
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
| | - Horst Neuhaus
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Thomas Rösch
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Ell
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | | | - Anne C. Böhmer
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
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Wikenius E, Moe V, Smith L, Heiervang ER, Berglund A. DNA methylation changes in infants between 6 and 52 weeks. Sci Rep 2019; 9:17587. [PMID: 31772264 PMCID: PMC6879561 DOI: 10.1038/s41598-019-54355-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/14/2019] [Indexed: 12/16/2022] Open
Abstract
Infants undergo extensive developments during their first year of life. Although the biological mechanisms involved are not yet fully understood, changes in the DNA methylation in mammals are believed to play a key role. This study was designed to investigate changes in infant DNA methylation that occurs between 6 and 52 weeks. A total of 214 infant saliva samples from 6 or 52 weeks were assessed using principal component analyses and t-distributed stochastic neighbor-embedding algorithms. Between the two time points, there were clear differences in DNA methylation. To further investigate these findings, paired two-sided student’s t-tests were performed. Differently methylated regions were defined as at least two consecutive probes that showed significant differences, with a q-value < 0.01 and a mean difference > 0.2. After correcting for false discovery rates, changes in the DNA methylation levels were found in 42 genes. Of these, 36 genes showed increased and six decreased DNA methylation. The overall DNA methylation changes indicated decreased gene expression. This was surprising because infants undergo such profound developments during their first year of life. The results were evaluated by taking into consideration the extensive development that occurs during pregnancy. During the first year of life, infants have an overall three-fold increase in weight, while the fetus develops from a single cell into a viable infant in 9 months, with an 875-million-fold increase in weight. It is possible that the findings represent a biological slowing mechanism in response to extensive fetal development. In conclusion, our study provides evidence of DNA methylation changes during the first year of life, representing a possible biological slowing mechanism. We encourage future studies of DNA methylation changes in infants to replicate the findings by using a repeated measures model and less stringent criteria to see if the same genes can be found, as well as investigating whether other genes are involved in development during this period.
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Affiliation(s)
- Ellen Wikenius
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Vibeke Moe
- Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway.,The Center for Child and Adolescent Mental Health, Eastern and Southern Norway (RBUP), Oslo, Norway
| | - Lars Smith
- Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway
| | - Einar R Heiervang
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Oslo University Hospital, Oslo, Norway
| | - Anders Berglund
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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Gastrointestinal dysfunction in autism displayed by altered motility and achalasia in Foxp1 +/- mice. Proc Natl Acad Sci U S A 2019; 116:22237-22245. [PMID: 31611379 DOI: 10.1073/pnas.1911429116] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal dysfunctions in individuals with autism spectrum disorder are poorly understood, although they are common among this group of patients. FOXP1 haploinsufficiency is characterized by autistic behavior, language impairment, and intellectual disability, but feeding difficulties and gastrointestinal problems have also been reported. Whether these are primary impairments, the result of altered eating behavior, or side effects of psychotropic medication remains unclear. To address this question, we investigated Foxp1 +/- mice reflecting FOXP1 haploinsufficiency. These animals show decreased body weight and altered feeding behavior with reduced food and water intake. A pronounced muscular atrophy was detected in the esophagus and colon, caused by reduced muscle cell proliferation. Nitric oxide-induced relaxation of the lower esophageal sphincter was impaired and achalasia was confirmed in vivo by manometry. Foxp1 targets (Nexn, Rbms3, and Wls) identified in the brain were dysregulated in the adult Foxp1 +/- esophagus. Total gastrointestinal transit was significantly prolonged due to impaired colonic contractility. Our results have uncovered a previously unknown dysfunction (achalasia and impaired gut motility) that explains the gastrointestinal disturbances in patients with FOXP1 syndrome, with potential wider relevance for autism.
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Dong J, Gharahkhani P, Chow WH, Gammon MD, Liu G, Caldas C, Wu AH, Ye W, Onstad L, Anderson LA, Bernstein L, Pharoah PD, Risch HA, Corley DA, Fitzgerald RC, Iyer PG, Reid BJ, Lagergren J, Shaheen NJ, Vaughan TL, MacGregor S, Love S, Palles C, Tomlinson I, Gockel I, May A, Gerges C, Anders M, Böhmer AC, Becker J, Kreuser N, Thieme R, Noder T, Venerito M, Veits L, Schmidt T, Schmidt C, Izbicki JR, Hölscher AH, Lang H, Lorenz D, Schumacher B, Mayershofer R, Vashist Y, Ott K, Vieth M, Weismüller J, Nöthen MM, Moebus S, Knapp M, Peters WHM, Neuhaus H, Rösch T, Ell C, Jankowski J, Schumacher J, Neale RE, Whiteman DC, Thrift AP. No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study. Clin Gastroenterol Hepatol 2019; 17:2227-2235.e1. [PMID: 30716477 PMCID: PMC6675666 DOI: 10.1016/j.cgh.2019.01.041] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Epidemiology studies of circulating concentrations of 25 hydroxy vitamin D (25(OH)D) and risk of esophageal adenocarcinoma (EAC) have produced conflicting results. We conducted a Mendelian randomization study to determine the associations between circulating concentrations of 25(OH)D and risks of EAC and its precursor, Barrett's esophagus (BE). METHODS We conducted a Mendelian randomization study using a 2-sample (summary data) approach. Six single-nucleotide polymorphisms (SNPs; rs3755967, rs10741657, rs12785878, rs10745742, rs8018720, and rs17216707) associated with circulating concentrations of 25(OH)D were used as instrumental variables. We collected data from 6167 patients with BE, 4112 patients with EAC, and 17,159 individuals without BE or EAC (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium, as well as studies from Bonn, Germany, and Cambridge and Oxford, United Kingdom. Analyses were performed separately for BE and EAC. RESULTS Overall, we found no evidence for an association between genetically estimated 25(OH)D concentration and risk of BE or EAC. The odds ratio per 20 nmol/L increase in genetically estimated 25(OH)D concentration for BE risk estimated by combining the individual SNP association using inverse variance weighting was 1.21 (95% CI, 0.77-1.92; P = .41). The odds ratio for EAC risk, estimated by combining the individual SNP association using inverse variance weighting, was 0.68 (95% CI, 0.39-1.19; P = .18). CONCLUSIONS In a Mendelian randomization study, we found that low genetically estimated 25(OH)D concentrations were not associated with risk of BE or EAC.
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Affiliation(s)
- Jing Dong
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Wong-Ho Chow
- Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas
| | - Marilie D Gammon
- Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina
| | - Geoffrey Liu
- Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada
| | - Carlos Caldas
- Cancer Research UK, Cambridge Institute, Cambridge, United Kingdom
| | - Anna H Wu
- Department of Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Lynn Onstad
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Lesley A Anderson
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland
| | - Leslie Bernstein
- Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California
| | - Paul D Pharoah
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, California; San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California
| | - Rebecca C Fitzgerald
- Medical Research Council Cancer Unit, Hutchison-Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Brian J Reid
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Nicholas J Shaheen
- Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Sharon Love
- Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Oxford, United Kingdom
| | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Ian Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Andrea May
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Christian Gerges
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Mario Anders
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany
| | - Anne C Böhmer
- Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
| | - Jessica Becker
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany; Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Rene Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Tania Noder
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Lothar Veits
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Claudia Schmidt
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
| | - Arnulf H Hölscher
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Dietmar Lorenz
- Department of General, Visceral and Thoracic Surgery, Klinikum Darmstadt, Darmstadt, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | | | - Yogesh Vashist
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany; Kantonsspital Aarau, Aarau, Switzerland
| | - Katja Ott
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | | | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
| | - Susanne Moebus
- Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, University of Essen, Essen, Germany
| | - Michael Knapp
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
| | - Wilbert H M Peters
- Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Horst Neuhaus
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Thomas Rösch
- Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Christian Ell
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | | | - Johannes Schumacher
- Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
| | - Rachel E Neale
- Cancer Aetiology and Prevention, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - David C Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Aaron P Thrift
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
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An J, Gharahkhani P, Law MH, Ong JS, Han X, Olsen CM, Neale RE, Lai J, Vaughan TL, Gockel I, Thieme R, Böhmer AC, Jankowski J, Fitzgerald RC, Schumacher J, Palles C, Whiteman DC, MacGregor S. Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases. Nat Commun 2019; 10:4219. [PMID: 31527586 PMCID: PMC6746768 DOI: 10.1038/s41467-019-11968-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.
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Affiliation(s)
- Jiyuan An
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Matthew H Law
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Jue-Sheng Ong
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Xikun Han
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Catherine M Olsen
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Rachel E Neale
- Cancer Aetiology and Prevention, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- School of Public Health, The University of Queensland, Brisbane, QLD, Australia
- School of Public Health and Social Work, the Queensland University of Technology, Brisbane, QLD, Australia
| | - John Lai
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia
| | - Tom L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Anne C Böhmer
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
| | | | - Rebecca C Fitzgerald
- Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, UK
| | - Johannes Schumacher
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Claire Palles
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - David C Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
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Callahan ZM, Shi Z, Su B, Xu J, Ujiki M. Genetic variants in Barrett's esophagus and esophageal adenocarcinoma: a literature review. Dis Esophagus 2019; 32:5393313. [PMID: 30888413 DOI: 10.1093/dote/doz017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Surveillance of Barrett's esophagus (BE) is a clinical challenge; metaplasia of the distal esophagus increases a patient's risk of esophageal adenocarcinoma (EAC) significantly but the actual percentage of patients who progress is low. The current screening recommendations require frequent endoscopy and biopsy, which has inherent risk, high cost, and operator variation. Identifying BE patients genetically who are at high risk of progressing could deemphasize the role of endoscopic screening and create an opportunity for early therapeutic intervention. Genetic alterations in germline DNA have been identified in other disease processes and allow for early intervention or surveillance well before disease develops. The genetic component of BE remains mostly unknown and only a few genome-wide association studies exist on this topic. This review summarizes the current literature available that examines genetic alterations in BE and EAC with a particular emphasis on clinical implications.
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Affiliation(s)
| | - Zhuqing Shi
- NorthShore University HealthSystem Research Institute
| | - Bailey Su
- Department of General Surgery, NorthShore University HealthSystem.,Department of General Surgery, University of Chicago, Chicago, USA
| | - Jianfeng Xu
- NorthShore University HealthSystem Research Institute
| | - Michael Ujiki
- Department of General Surgery, NorthShore University HealthSystem
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Li S, Chung DC, Mullen JT. Screening high-risk populations for esophageal and gastric cancer. J Surg Oncol 2019; 120:831-846. [PMID: 31373005 DOI: 10.1002/jso.25656] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 07/17/2019] [Indexed: 12/17/2022]
Abstract
Cancers of the esophagus and stomach remain important causes of mortality worldwide, in large part because they are most often diagnosed at advanced stages. Thus, it is imperative that we identify and treat these cancers in earlier stages. Due to significant heterogeneity in incidence and risk factors for these cancers, it has been challenging to develop standardized screening recommendations. This review summarizes the current recommendations for screening populations at high risk of developing esophagogastric cancers.
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Affiliation(s)
- Selena Li
- Departments of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Daniel C Chung
- Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - John T Mullen
- Departments of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Argyrou A, Legaki E, Koutserimpas C, Gazouli M, Papaconstantinou I, Gkiokas G, Karamanolis G. Polymorphisms of the BARX1 and ADAMTS17 Locus Genes in Individuals With Gastroesophageal Reflux Disease. J Neurogastroenterol Motil 2019; 25:436-441. [PMID: 31048564 PMCID: PMC6657930 DOI: 10.5056/jnm18183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/01/2019] [Accepted: 04/07/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Gastroesophageal reflux disease (GERD) represents a common condition having a substantial impact on the patients' quality of life, as well as the health system. According to many studies, the BARX1 and ADAMTS17 genes have been suggested as genetic risk loci for the development of GERD and its complications. The purpose of this study is to investigate the potential association between GERD and BARX1 and ADAMTS17 polymorphisms. METHODS The present is a prospective cohort study of 160 GERD patients and 180 healthy control subjects of Greek origin, examined for BARX1 and ADAMTS17 polymorphisms (rs11789015 and rs4965272) and a potential correlation to GERD. RESULTS The rs11789015 AG and GG genotypes were found to be significantly associated with GERD (P= 0.032; OR, 1.65; 95% CI, 1.062.57 and P= 0.033; OR, 3.00; 95% CI, 1.15-7.82, respectively), as well as the G allele (P= 0.007; OR, 1.60; 95% CI, 1.14- 2.24). Concerning the rs4965272, only the GG genotype was significantly associated with GERD (P= 0.035; OR, 3.42; 95% CI, 1.06-11.05). CONCLUSIONS This is a study investigating the potential correlation between BARX1 and ADAMTS17 polymorphisms and the development of GERD, showing a considerable association between both polymorphisms and the disease. This finding suggests that esophageal differentiation or altered regulation on microfibrils in the cell environment could be implicated as possible mechanisms in the pathogenesis of GERD.
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Affiliation(s)
- Alexandra Argyrou
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - Evangelia Legaki
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - Christos Koutserimpas
- 2nd Department of General Surgery, “Sismanoglio General Hospital of Athens, Athens,
Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - Ioannis Papaconstantinou
- 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - George Gkiokas
- 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
| | - George Karamanolis
- Gastroenterology Unit, 2nd Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece
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Abstract
OBJECTIVES Several single-nucleotide polymorphisms (SNPs) have been associated with Barrett's esophagus (BE) risk. In addition, environmental factors including smoking, alcohol consumption, and heartburn increase BE risk. However, data on potential interactions between these genetic and environmental factors on BE risk are scant. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE, and potentially identify opportunities for targeted prevention and treatment. The objectives of this study were to examine the main effects and the potential effect modification between known genetic loci (SNPs) and established environmental risk factors for BE. METHODS We performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. Overall, we genotyped 46 SNPs identified in previous BE genome-wide association studies as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed. RESULTS We observed a suggestive, but not statistically significant, association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of BE by a factor of 1.20 (95% confidence interval = 1.00-1.44; P = 0.057). We did not observe any meaningful multiplicative interactions between smoking, alcohol consumption, or heartburn duration and BE genotypes. When we assessed the joint effect of weighted GRS and BE risk factors, we did not observe any significant interaction with alcohol and heartburn duration, whereas smoking showed a significant multiplicative interaction (P = 0.016). CONCLUSIONS Our results suggest that SNPs associated with BE at genome-wide significant levels can be combined into a GRS with a potential positive association with BE risk.
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Guo X, Zhao L, Shen Y, Shao Y, Wei W, Liu F. Polymorphism of miRNA and esophageal cancer risk: an updated systemic review and meta-analysis. Onco Targets Ther 2019; 12:3565-3580. [PMID: 31213825 PMCID: PMC6537464 DOI: 10.2147/ott.s193958] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 04/03/2019] [Indexed: 12/24/2022] Open
Abstract
Background: Accumulating evidence has demonstrated that single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) (referred to as miR-SNPs) participate in the process of carcinogenesis by altering the expression and structure of mature miRNAs. However, the associations between several previously reported miR-SNPs, including miR-196a2 rs11614913, miR-146a rs2910164, miR-34b/c rs4938723, and miR-423 rs6505162 and the susceptibility of esophageal squamous cell carcinoma (ESCC) remain controversial. We, therefore, performed a comprehensive meta-analysis to systemically evaluate the correlation of genetic polymorphisms in these four miRNAs with the risk of ESCC. Methods: Relevant studies were searched in PubMed and other electronic databases up to August 2018, supplemented by a manual search of references from retrieved articles. The pooled ORs with 95% CIs were calculated using a random-effects model. Results: A total of 22 studies from 13 published articles were included in the meta-analysis. All studies have a relatively high score of quality assessment. The pooled analysis indicated that individuals with the variant TT genotype of rs11614913 in miR-196a2 gene have a significantly decreased risk of ESCC compared with CC genotype (OR =0.83, 95% CI: 0.73–0.95). The decreased risk of ESCC was also shown in the recessive model (TT vs CT/CC: OR=0.86, 95%CI: 0.77–0.96) and allele model (T vs C: OR=0.93, 95%CI: 0.87–0.99). The significantly reduced risk of ESCC was also observed in the polymorphisms of the miR-34b/c rs4938723 locus. The similar tendency was presented in the subgroup of Chinese Han population when stratified by ethnicity. However, no significant associations were observed in the miR-146a rs2910164 and miR-423 rs6505162 with the susceptibility of ESCC in any genetic model. Conclusion: Our results suggested that the polymorphisms of miR-196a and miR-34b/c genes were related to the risk of ESCC, especially among Chinese. The findings of this study, however, need to be confirmed in further researches.
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Affiliation(s)
- Xudong Guo
- Department of Epidemiology and Health Statistics, School of Public Health, Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing 100069, People's Republic of China
| | - Lei Zhao
- Department of Molecular Physiology and Biophysics, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Yi Shen
- Department of Epidemiology and Health Statistics, School of Public Health, Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing 100069, People's Republic of China
| | - Yi Shao
- Department of Epidemiology and Health Statistics, School of Public Health, Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing 100069, People's Republic of China
| | - Wenqiang Wei
- National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100021, People's Republic of China
| | - Fen Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Beijing Municipal Key Laboratory of Clinical Epidemiology, Capital Medical University, Beijing 100069, People's Republic of China
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Miga KH. Centromeric Satellite DNAs: Hidden Sequence Variation in the Human Population. Genes (Basel) 2019; 10:E352. [PMID: 31072070 PMCID: PMC6562703 DOI: 10.3390/genes10050352] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/03/2019] [Accepted: 05/03/2019] [Indexed: 12/30/2022] Open
Abstract
The central goal of medical genomics is to understand the inherited basis of sequence variation that underlies human physiology, evolution, and disease. Functional association studies currently ignore millions of bases that span each centromeric region and acrocentric short arm. These regions are enriched in long arrays of tandem repeats, or satellite DNAs, that are known to vary extensively in copy number and repeat structure in the human population. Satellite sequence variation in the human genome is often so large that it is detected cytogenetically, yet due to the lack of a reference assembly and informatics tools to measure this variability, contemporary high-resolution disease association studies are unable to detect causal variants in these regions. Nevertheless, recently uncovered associations between satellite DNA variation and human disease support that these regions present a substantial and biologically important fraction of human sequence variation. Therefore, there is a pressing and unmet need to detect and incorporate this uncharacterized sequence variation into broad studies of human evolution and medical genomics. Here I discuss the current knowledge of satellite DNA variation in the human genome, focusing on centromeric satellites and their potential implications for disease.
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Affiliation(s)
- Karen H Miga
- UC Santa Cruz Genomics Institute, University of California, Santa Cruz, California, CA 95064, USA.
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50
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Konda VJA, Souza RF. Barrett's Esophagus and Esophageal Carcinoma: Can Biomarkers Guide Clinical Practice? Curr Gastroenterol Rep 2019; 21:14. [PMID: 30868278 DOI: 10.1007/s11894-019-0685-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
PURPOSE OF REVIEW Despite gastrointestinal societal recommendations for endoscopic screening and surveillance of Barrett's esophagus, the rates of esophageal adenocarcinoma continue to rise. Furthermore, this current practice is costly to patients and the medical system without clear evidence of reduction in cancer mortality. The use of biomarkers to guide screening, surveillance, and treatment strategies might alleviate some of these issues. RECENT FINDINGS Incredible advances in biomarker identification, biomarker assays, and minimally-invasive modalities to acquire biomarkers have shown promising results. We will highlight recently published, key studies demonstrating where we are with using biomarkers for screening and surveillance in clinical practice, and what is on the horizon regarding novel non-invasive and minimally invasive methods to acquire biomarkers. Proof-of principle studies using in silico models demonstrate that biomarker-guided screening, surveillance, and therapeutic intervention strategies can be cost-effective and can reduce cancer deaths in patients with Barrett's esophagus.
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Affiliation(s)
- Vani J A Konda
- Department of Medicine and the Center for Esophageal Diseases, Baylor University Medical Center, Dallas, TX, 75246, USA
- The Center for Esophageal Research, Baylor Scott and White Research Institute, Baylor University Medical Center, 2 Hoblitzelle, Suite 250, 3500 Gaston Avenue, Dallas, TX, 75246, USA
| | - Rhonda F Souza
- Department of Medicine and the Center for Esophageal Diseases, Baylor University Medical Center, Dallas, TX, 75246, USA.
- The Center for Esophageal Research, Baylor Scott and White Research Institute, Baylor University Medical Center, 2 Hoblitzelle, Suite 250, 3500 Gaston Avenue, Dallas, TX, 75246, USA.
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