Grant Details
Grant Number: |
1R01CA136725-01A1 Interpret this number |
Primary Investigator: |
Vaughan, Thomas |
Organization: |
Fred Hutchinson Cancer Research Center |
Project Title: |
Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) |
Fiscal Year: |
2009 |
Abstract
DESCRIPTION (provided by applicant): The incidence of esophageal adenocarcinoma (EA), a rapidly fatal disease, has increased faster than any other cancer in the US over the last three decades - over 500 percent. Gastroesophageal reflux and obesity have been found to be key modifiable risk factors for the development of EA and its main precursor, Barrett's esophagus (BE). However, while reflux appears to be crucial to the neoplastic process, only about 10 - 15 percent of individuals with long-standing reflux symptoms develop BE in their lifetimes; among those who do, most do not progress to EA. Similarly, the mechanisms by which obesity increases risk of EA are not known. Thus, there must be other cofactors modulating the reflux-related chronic inflammatory effects on the esophageal epithelium and the local and systemic consequences of being overweight, that largely determine risk. Many of these cofactors are likely to be genetically mediated, and while family, twin and candidate gene studies support this notion, no genes have been established yet as playing a causal role. Here, we propose a large-scale genome-wide association study which takes advantage of the extensive data collected by investigators in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) in 18 epidemiologic studies, representing the vast majority of the well-designed largely population-based studies of these diseases in the world. The overall goal of our research is to evaluate the influence of genetic susceptibility on risk of EA and BE. The primary aim is to identify tagSNPs most strongly associated with risk of BE and EA. In secondary aims we will evaluate the extent to which the most significant associations vary according to key environmental and host risk factors for these conditions, including gender, obesity and cigarette smoking. We propose a single phase approach over three years involving 7,500 participants, all of whom have been previously interviewed regarding major environmental and host risk factors and have donated blood specimens. The Illumina Infinium Human 610-Quad Chip will be used to genotype approximately 1,500 cases of EA, 3,000 cases of BE and 3,000 population controls. Additional sources of samples and data have been identified to provide replication studies (funding to be requested separately.) The resources of BEACON, together with recent advances in genomic technology and analytic methods, present a unique and cost-effective opportunity to a) study the influence of genetic and environmental factors in the etiology of these important diseases, b) aid in the identification of key biological pathways in their pathogenesis, and c) help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively. PUBLIC HEALTH RELEVANCE: The incidence of esophageal adenocarcinoma, a rapidly fatal disease, has increased more than six-fold over the past 30 years. By conducting a large-scale genome-wide association study using pooled data and DNA from 18 epidemiologic studies, we propose to evaluate the influence of genetic susceptibility on risk of this cancer and its main precancerous condition, Barrett's esophagus, and determine the extent to which susceptibility factors vary according to key environmental and host risk factors for these conditions. These results will aid in the identification of biological pathways important in the etiology of this cancer, and help target persons at highest risk so that screening, prevention and surveillance efforts can be directed most effectively.
Publications
A risk variant for Barrett's esophagus and esophageal adenocarcinoma at chr8p23.1 affects enhancer activity and implicates multiple gene targets.
Authors: Ali M.W.
, Chen J.
, Yan L.
, Wang X.
, Dai J.Y.
, Vaughan T.L.
, Casey G.
, Buas M.F.
.
Source: Human Molecular Genetics, 2022-11-28 00:00:00.0; 31(23), p. 3975-3986.
PMID: 35766871
Related Citations
Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.
Authors: Ong J.S.
, An J.
, Han X.
, Law M.H.
, Nandakumar P.
, 23andMe Research team
, Esophageal cancer consortium
, Schumacher J.
, Gockel I.
, Bohmer A.
, et al.
.
Source: Gut, 2022 06; 71(6), p. 1053-1061.
EPub date: 2021-06-29 00:00:00.0.
PMID: 34187846
Related Citations
Prioritization and functional analysis of GWAS risk loci for Barrett's esophagus and esophageal adenocarcinoma.
Authors: Chen J.
, Ali M.W.
, Yan L.
, Dighe S.G.
, Dai J.Y.
, Vaughan T.L.
, Casey G.
, Buas M.F.
.
Source: Human Molecular Genetics, 2022-02-03 00:00:00.0; 31(3), p. 410-422.
PMID: 34505128
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Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study.
Authors: Chia R.
, Saez-Atienzar S.
, Murphy N.
, Chiò A.
, Blauwendraat C.
, International Myasthenia Gravis Genomics Consortium
, Roda R.H.
, Tienari P.J.
, Kaminski H.J.
, Ricciardi R.
, et al.
.
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2022-02-01 00:00:00.0; 119(5), .
PMID: 35074870
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Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.
Authors: Dighe S.G.
, Chen J.
, Yan L.
, He Q.
, Gharahkhani P.
, Onstad L.
, Levine D.M.
, Palles C.
, Ye W.
, Gammon M.D.
, et al.
.
Source: Carcinogenesis, 2021-04-17 00:00:00.0; 42(3), p. 369-377.
PMID: 33300568
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Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types.
Authors: Saez-Atienzar S.
, Bandres-Ciga S.
, Langston R.G.
, Kim J.J.
, Choi S.W.
, Reynolds R.H.
, International ALS Genomics Consortium
, ITALSGEN
, Abramzon Y.
, Dewan R.
, et al.
.
Source: Science Advances, 2021 01; 7(3), .
EPub date: 2021-01-15 00:00:00.0.
PMID: 33523907
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Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.
Authors: Dong J.
, Maj C.
, Tsavachidis S.
, Ostrom Q.T.
, Gharahkhani P.
, Anderson L.A.
, Wu A.H.
, Ye W.
, Bernstein L.
, Borisov O.
, et al.
.
Source: Gastroenterology, 2020 12; 159(6), p. 2065-2076.e1.
EPub date: 2020-09-09 00:00:00.0.
PMID: 32918910
Related Citations
Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases.
Authors: An J.
, Gharahkhani P.
, Law M.H.
, Ong J.S.
, Han X.
, Olsen C.M.
, Neale R.E.
, Lai J.
, Vaughan T.L.
, Böhmer A.C.
, et al.
.
Source: Nature Communications, 2019-09-16 00:00:00.0; 10(1), p. 4219.
EPub date: 2019-09-16 00:00:00.0.
PMID: 31527586
Related Citations
No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study.
Authors: Dong J.
, Gharahkhani P.
, Chow W.H.
, Gammon M.D.
, Liu G.
, Caldas C.
, Wu A.H.
, Ye W.
, Onstad L.
, Anderson L.A.
, et al.
.
Source: Clinical Gastroenterology And Hepatology : The Official Clinical Practice Journal Of The American Gastroenterological Association, 2019-02-01 00:00:00.0; , .
EPub date: 2019-02-01 00:00:00.0.
PMID: 30716477
Related Citations
Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus.
Authors: Dong J.
, Levine D.M.
, Buas M.F.
, Zhang R.
, Onstad L.
, Fitzgerald R.C.
, Stomach and Oesophageal Cancer Study (SOCS) Consortium
, Corley D.A.
, Shaheen N.J.
, Lagergren J.
, et al.
.
Source: Clinical Gastroenterology And Hepatology : The Official Clinical Practice Journal Of The American Gastroenterological Association, 2018 Oct; 16(10), p. 1598-1606.e4.
EPub date: 2018-03-15 00:00:00.0.
PMID: 29551738
Related Citations
Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma.
Authors: Gharahkhani P.
, Burdon K.P.
, Cooke Bailey J.N.
, Hewitt A.W.
, Law M.H.
, Pasquale L.R.
, Kang J.H.
, Haines J.L.
, Souzeau E.
, Zhou T.
, et al.
.
Source: Scientific Reports, 2018-02-15 00:00:00.0; 8(1), p. 3124.
EPub date: 2018-02-15 00:00:00.0.
PMID: 29449654
Related Citations
Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.
Authors: Bailey J.N.C.
, Gharahkhani P.
, Kang J.H.
, Butkiewicz M.
, Sullivan D.A.
, Weinreb R.N.
, Aschard H.
, Allingham R.R.
, Ashley-Koch A.
, Lee R.K.
, et al.
.
Source: Investigative Ophthalmology & Visual Science, 2018-02-01 00:00:00.0; 59(2), p. 629-636.
PMID: 29392307
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Whole-genome sequencing of esophageal adenocarcinoma in Chinese patients reveals distinct mutational signatures and genomic alterations.
Authors: Dai J.Y.
, Wang X.
, Buas M.F.
, Zhang C.
, Ma J.
, Wei B.
, Li Y.
, Zhao B.
, Hyun T.S.
, Chen X.
, et al.
.
Source: Communications Biology, 2018; 1, p. 174.
EPub date: 2018-10-24 00:00:00.0.
PMID: 30374464
Related Citations
Determining Risk of Barrett's Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants.
Authors: Dong J.
, Buas M.F.
, Gharahkhani P.
, Kendall B.J.
, Onstad L.
, Zhao S.
, Anderson L.A.
, Wu A.H.
, Ye W.
, Bird N.C.
, et al.
.
Source: Gastroenterology, 2017-12-13 00:00:00.0; , .
EPub date: 2017-12-13 00:00:00.0.
PMID: 29247777
Related Citations
The Evolving Genomic Landscape of Barrett's Esophagus and Esophageal Adenocarcinoma.
Authors: Contino G.
, Vaughan T.L.
, Whiteman D.
, Fitzgerald R.C.
.
Source: Gastroenterology, 2017 09; 153(3), p. 657-673.e1.
EPub date: 2017-07-14 00:00:00.0.
PMID: 28716721
Related Citations
Genome-wide Association Studies In Oesophageal Adenocarcinoma And Barrett's Oesophagus: A Large-scale Meta-analysis
Authors: Gharahkhani P.
, Fitzgerald R.C.
, Vaughan T.L.
, Palles C.
, Gockel I.
, Tomlinson I.
, Buas M.F.
, May A.
, Gerges C.
, Anders M.
, et al.
.
Source: The Lancet. Oncology, 2016 Oct; 17(10), p. 1363-1373.
PMID: 27527254
Related Citations
Constrained Score Statistics Identify Genetic Variants Interacting with Multiple Risk Factors in Barrett's Esophagus.
Authors: Dai J.Y.
, Tapsoba J.D.
, Buas M.F.
, BEACON Consortium
, Risch H.A.
, Vaughan T.L.
.
Source: American Journal Of Human Genetics, 2016-08-04 00:00:00.0; 99(2), p. 352-65.
PMID: 27486777
Related Citations
Germline Variation In Inflammation-related Pathways And Risk Of Barrett's Oesophagus And Oesophageal Adenocarcinoma
Authors: Buas M.F.
, He Q.
, Johnson L.G.
, Onstad L.
, Levine D.M.
, Thrift A.P.
, Gharahkhani P.
, Palles C.
, Lagergren J.
, Fitzgerald R.C.
, et al.
.
Source: Gut, 2016-08-02 00:00:00.0; , .
PMID: 27486097
Related Citations
Variants Of Ever1 And Ever2 (tmc6 And Tmc8) And Human Papillomavirus Status In Patients With Mucosal Squamous Cell Carcinoma Of The Head And Neck
Authors: Antonsson A.
, Law M.H.
, Neale R.E.
, Coman W.B.
, Pryor D.I.
, Study of Digestive Health (SDH)
, Porceddu S.V.
, Whiteman D.C.
.
Source: Cancer Causes & Control : Ccc, 2016 06; 27(6), p. 809-15.
PMID: 27097911
Related Citations
Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.
Authors: Ek W.E.
, Lagergren K.
, Cook M.
, Wu A.H.
, Abnet C.C.
, Levine D.
, Chow W.H.
, Bernstein L.
, Risch H.A.
, Shaheen N.J.
, et al.
.
Source: International Journal Of Cancer, 2016-03-01 00:00:00.0; 138(5), p. 1146-52.
EPub date: 2016-03-01 00:00:00.0.
PMID: 26414697
Related Citations
Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus.
Authors: Gharahkhani P.
, Tung J.
, Hinds D.
, Mishra A.
, Barrett's and Esophageal Adenocarcinoma Consortium (BEACON)
, Vaughan T.L.
, Whiteman D.C.
, MacGregor S.
, BEACON study investigators
.
Source: Human Molecular Genetics, 2016-02-15 00:00:00.0; 25(4), p. 828-35.
EPub date: 2016-02-15 00:00:00.0.
PMID: 26704365
Related Citations
Pleiotropic Analysis Of Cancer Risk Loci On Esophageal Adenocarcinoma Risk
Authors: Lee E.
, Stram D.O.
, Ek W.E.
, Onstad L.E.
, MacGregor S.
, Gharahkhani P.
, Ye W.
, Lagergren J.
, Shaheen N.J.
, Murray L.J.
, et al.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2015 Nov; 24(11), p. 1801-3.
PMID: 26364162
Related Citations
A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett's esophagus.
Authors: Dai J.Y.
, de Dieu Tapsoba J.
, Buas M.F.
, Onstad L.E.
, Levine D.M.
, Risch H.A.
, Chow W.H.
, Bernstein L.
, Ye W.
, Lagergren J.
, et al.
.
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2015 Nov; 24(11), p. 1739-47.
PMID: 26377193
Related Citations
Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus.
Authors: Li X.
, Paulson T.G.
, Galipeau P.C.
, Sanchez C.A.
, Liu K.
, Kuhner M.K.
, Maley C.C.
, Self S.G.
, Vaughan T.L.
, Reid B.J.
, et al.
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2015 Sep; 8(9), p. 845-56.
PMID: 26130253
Related Citations
Accurate Imputation-based Screening Of Gln368ter Myocilin Variant In Primary Open-angle Glaucoma
Authors: Gharahkhani P.
, Burdon K.P.
, Hewitt A.W.
, Law M.H.
, Souzeau E.
, Montgomery G.W.
, Radford-Smith G.
, Mackey D.A.
, Craig J.E.
, MacGregor S.
.
Source: Investigative Ophthalmology & Visual Science, 2015 Aug; 56(9), p. 5087-93.
PMID: 26237198
Related Citations
A Common Variant Near Tgfbr3 Is Associated With Primary Open Angle Glaucoma
Authors: Li Z.
, Allingham R.R.
, Nakano M.
, Jia L.
, Chen Y.
, Ikeda Y.
, Mani B.
, Chen L.J.
, Kee C.
, Garway-Heath D.F.
, et al.
.
Source: Human Molecular Genetics, 2015-07-01 00:00:00.0; 24(13), p. 3880-92.
PMID: 25861811
Related Citations
Precision Prevention Of Oesophageal Adenocarcinoma
Authors: Vaughan T.L.
, Fitzgerald R.C.
.
Source: Nature Reviews. Gastroenterology & Hepatology, 2015 Apr; 12(4), p. 243-8.
PMID: 25666644
Related Citations
Polymorphisms Near Tbx5 And Gdf7 Are Associated With Increased Risk For Barrett's Esophagus
Authors: Palles C.
, Chegwidden L.
, Li X.
, Findlay J.M.
, Farnham G.
, Castro Giner F.
, Peppelenbosch M.P.
, Kovac M.
, Adams C.L.
, Prenen H.
, et al.
.
Source: Gastroenterology, 2015 Feb; 148(2), p. 367-78.
PMID: 25447851
Related Citations
MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium.
Authors: Buas M.F.
, Onstad L.
, Levine D.M.
, Risch H.A.
, Chow W.H.
, Liu G.
, Fitzgerald R.C.
, Bernstein L.
, Ye W.
, Bird N.C.
, et al.
.
Source: Plos One, 2015; 10(6), p. e0128617.
EPub date: 2015-06-03 00:00:00.0.
PMID: 26039359
Related Citations
Bacterial Composition Of The Human Upper Gastrointestinal Tract Microbiome Is Dynamic And Associated With Genomic Instability In A Barrett's Esophagus Cohort
Authors: Gall A.
, Fero J.
, McCoy C.
, Claywell B.C.
, Sanchez C.A.
, Blount P.L.
, Li X.
, Vaughan T.L.
, Matsen F.A.
, Reid B.J.
, et al.
.
Source: Plos One, 2015; 10(6), p. e0129055.
PMID: 26076489
Related Citations
Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium.
Authors: Lagergren K.
, Ek W.E.
, Levine D.
, Chow W.H.
, Bernstein L.
, Casson A.G.
, Risch H.A.
, Shaheen N.J.
, Bird N.C.
, Reid B.J.
, et al.
.
Source: Plos One, 2015; 10(9), p. e0138738.
PMID: 26406593
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Integrative Post-genome-wide Association Analysis Of Cdkn2a And Tp53 Snps And Risk Of Esophageal Adenocarcinoma
Authors: Buas M.F.
, Levine D.M.
, Makar K.W.
, Utsugi H.
, Onstad L.
, Li X.
, Galipeau P.C.
, Shaheen N.J.
, Hardie L.J.
, Romero Y.
, et al.
.
Source: Carcinogenesis, 2014 Dec; 35(12), p. 2740-7.
PMID: 25280564
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Most Common 'sporadic' Cancers Have A Significant Germline Genetic Component
Authors: Lu Y.
, Ek W.E.
, Whiteman D.
, Vaughan T.L.
, Spurdle A.B.
, Easton D.F.
, Pharoah P.D.
, Thompson D.J.
, Dunning A.M.
, Hayward N.K.
, et al.
.
Source: Human Molecular Genetics, 2014-11-15 00:00:00.0; 23(22), p. 6112-8.
PMID: 24943595
Related Citations
Obesity and risk of esophageal adenocarcinoma and Barrett's esophagus: a Mendelian randomization study.
Authors: Thrift A.P.
, Shaheen N.J.
, Gammon M.D.
, Bernstein L.
, Reid B.J.
, Onstad L.
, Risch H.A.
, Liu G.
, Bird N.C.
, Wu A.H.
, et al.
.
Source: Journal Of The National Cancer Institute, 2014 Nov; 106(11), .
PMID: 25269698
Related Citations
Risk of esophageal adenocarcinoma decreases with height, based on consortium analysis and confirmed by Mendelian randomization.
Authors: Thrift A.P.
, Risch H.A.
, Onstad L.
, Shaheen N.J.
, Casson A.G.
, Bernstein L.
, Corley D.A.
, Levine D.M.
, Chow W.H.
, Reid B.J.
, et al.
.
Source: Clinical Gastroenterology And Hepatology : The Official Clinical Practice Journal Of The American Gastroenterological Association, 2014 Oct; 12(10), p. 1667-76.e1.
PMID: 24530603
Related Citations
Common Variants Near Abca1, Afap1 And Gmds Confer Risk Of Primary Open-angle Glaucoma
Authors: Gharahkhani P.
, Burdon K.P.
, Fogarty R.
, Sharma S.
, Hewitt A.W.
, Martin S.
, Law M.H.
, Cremin K.
, Bailey J.N.
, Loomis S.J.
, et al.
.
Source: Nature Genetics, 2014 Oct; 46(10), p. 1120-5.
PMID: 25173105
Related Citations
From Genomics To Diagnostics Of Esophageal Adenocarcinoma
Authors: Vaughan T.L.
.
Source: Nature Genetics, 2014 Aug; 46(8), p. 806-7.
PMID: 25070798
Related Citations
Family History Of Cancer And Gastroesophageal Disorders And Risk Of Esophageal And Gastric Adenocarcinomas: A Case-control Study
Authors: Jiang X.
, Tseng C.C.
, Bernstein L.
, Wu A.H.
.
Source: Bmc Cancer, 2014; 14, p. 60.
PMID: 24495377
Related Citations
Quantification Of Population Benefit In Evaluation Of Biomarkers: Practical Implications For Disease Detection And Prevention
Authors: Li X.
, Blount P.L.
, Reid B.J.
, Vaughan T.L.
.
Source: Bmc Medical Informatics And Decision Making, 2014; 14, p. 15.
PMID: 24602132
Related Citations
A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.
Authors: Levine D.M.
, Ek W.E.
, Zhang R.
, Liu X.
, Onstad L.
, Sather C.
, Lao-Sirieix P.
, Gammon M.D.
, Corley D.A.
, Shaheen N.J.
, et al.
.
Source: Nature Genetics, 2013 Dec; 45(12), p. 1487-93.
PMID: 24121790
Related Citations
Germline Genetic Contributions To Risk For Esophageal Adenocarcinoma, Barrett's Esophagus, And Gastroesophageal Reflux
Authors: Ek W.E.
, Levine D.M.
, D'Amato M.
, Pedersen N.L.
, Magnusson P.K.
, Bresso F.
, Onstad L.E.
, Schmidt P.T.
, Törnblom H.
, Nordenstedt H.
, et al.
.
Source: Journal Of The National Cancer Institute, 2013-11-20 00:00:00.0; 105(22), p. 1711-8.
PMID: 24168968
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Epidemiology And Risk Factors For Gastroesophageal Junction Tumors: Understanding The Rising Incidence Of This Disease
Authors: Buas M.F.
, Vaughan T.L.
.
Source: Seminars In Radiation Oncology, 2013 Jan; 23(1), p. 3-9.
PMID: 23207041
Related Citations
Common Variants At The Mhc Locus And At Chromosome 16q24.1 Predispose To Barrett's Esophagus
Authors: Su Z.
, Gay L.J.
, Strange A.
, Palles C.
, Band G.
, Whiteman D.C.
, Lescai F.
, Langford C.
, Nanji M.
, Edkins S.
, et al.
.
Source: Nature Genetics, 2012 Oct; 44(10), p. 1131-6.
PMID: 22961001
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A Clinical Risk Prediction Model For Barrett Esophagus
Authors: Thrift A.P.
, Kendall B.J.
, Pandeya N.
, Vaughan T.L.
, Whiteman D.C.
, Study of Digestive Health
.
Source: Cancer Prevention Research (philadelphia, Pa.), 2012 Sep; 5(9), p. 1115-23.
PMID: 22787114
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