title: Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma.
abstract: Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3'UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility.
authors.affiliation: Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA 98109, USA, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, mbuas@fhcrc.org.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Buas
authors.affiliation: Department of Biostatistics, University of Washington, School of Public Health, Seattle, WA 98109, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Levine
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Utsugi
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Onstad
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Galipeau
authors.affiliation: Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shaheen
authors.affiliation: Division of Epidemiology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hardie
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MI 55905, USA, The Romero Registry, Mayo Clinic, Rochester, MI 55905, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Department of Populations Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.affiliation: Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, NC 27599, USA.
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.affiliation: Department of Surgery, University of Saskatchewan, Saskatoon S7N 5E5, Canada.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Casson
authors.affiliation: Department of Oncology, Medical School, University of Sheffield, Sheffield S10 2RX UK.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Bird
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06510, USA.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ye
authors.affiliation: Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612 USA, San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, CA 94115 USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Corley
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Blount
authors.affiliation: Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge CB2 0XZ UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
authors.affiliation: Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane Queensland 4006, Australia and.
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.affiliation: Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Reid
authors.affiliation: Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA 98109, USA, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53