Format

Send to:

Choose Destination
See comment in PubMed Commons below
Carcinogenesis. 2014 Dec;35(12):2740-7. doi: 10.1093/carcin/bgu207. Epub 2014 Oct 3.

Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma.

Author information

  • 1Department 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.
  • 2Department of Biostatistics, University of Washington, School of Public Health, Seattle, WA 98109, USA.
  • 3Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • 4Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • 5Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 6Division of Epidemiology, University of Leeds, Leeds LS2 9JT, UK.
  • 7Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MI 55905, USA, The Romero Registry, Mayo Clinic, Rochester, MI 55905, USA.
  • 8Department of Populations Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
  • 9Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, NC 27599, USA.
  • 10Department of Surgery, University of Saskatchewan, Saskatoon S7N 5E5, Canada.
  • 11Department of Oncology, Medical School, University of Sheffield, Sheffield S10 2RX UK.
  • 12Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06510, USA.
  • 13Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.
  • 14Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada.
  • 15Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612 USA, San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, CA 94115 USA.
  • 16Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge CB2 0XZ UK.
  • 17Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane Queensland 4006, Australia and.
  • 18Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
  • 19Division 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.
  • 20Department 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.

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.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PMID:
25280564
[PubMed - indexed for MEDLINE]
PMCID:
PMC4247522
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk