title: Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.
abstract: The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.|Statistical Genetics, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: Weronica E
authors.initials: WE
authors.lastname: Ek
authors.affiliation: Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lagergren
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
authors.forename: Michael
authors.initials: M
authors.lastname: Cook
authors.affiliation: Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Abnet
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA.
authors.forename: David
authors.initials: D
authors.lastname: Levine
authors.affiliation: Department of Epidemiology, MD Anderson Cancer Center, Houston, TX.
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.affiliation: Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.affiliation: Yale School of Public Health, New Haven, CT.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.affiliation: Division of Gastroenterology and Hepatology, UNC School of Medicine, University of North Carolina, Chapel Hill, NC.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shaheen
authors.affiliation: Department of Oncology, The Medical School, University of Sheffield, United Kingdom.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Bird
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, CA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Corley
authors.affiliation: Division of Epidemiology, University of Leeds, United Kingdom.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hardie
authors.affiliation: Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, United Kingdom.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, NC.
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Departments of Medicine, Epidemiology, and Medical Biophysics, Princess Margaret Cancer Centre, Dalla Lana School of Public Health, University of Toronto, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ye
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Cancer Control Group, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Westberg
authors.affiliation: Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.|Division of Cancer Studies, King's College London, United Kingdom.
authors.forename: Jesper
authors.initials: J
authors.lastname: Lagergren
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000209:etiology / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
chemical_list: C520448:JMJD1C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D010089:Oxidoreductases, N-Demethylating
keywords: Barrett esophagus; esophageal neoplasms; genome-wide association study; gonadal steroid hormone; hormones; neoplasm