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Carcinogenesis Advance Access published online on May 5, 2005
Carcinogenesis, doi:10.1093/carcin/bgi115
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 14, 2005
Revised April 21, 2005
Accepted April 26, 2005

CANCER BIOLOGY

Polymorphisms in DNA repair genes in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma

Alan G. Casson 1*, Zuoyu Zheng 2, Susan C. Evans 2, Paul J. Veugelers 3, Geoffrey A. Porter 4, and Duane L. Guernsey 1

1 Department of Surgery, Division of Molecular Pathology and Molecular Genetics, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Pathology, Division of Molecular Pathology and Molecular Genetics, Dalhousie University, Halifax, Nova Scotia, Canada
2 Department of Pathology, Division of Molecular Pathology and Molecular Genetics, Dalhousie University, Halifax, Nova Scotia, Canada
3 Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, Canada
4 Department of Surgery, Division of Molecular Pathology and Molecular Genetics, Dalhousie University, Halifax, Nova Scotia, Canada

* To whom correspondence should be addressed.
Alan G. Casson, E-mail: alan.casson{at}dal.ca


  Abstract

To test the hypothesis that aberrations of DNA repair contribute to susceptibility for the progression of gastroesophageal reflux disease (GERD) to Barrett esophagus (BE) and esophageal adenocarcinoma (EADC), we studied the frequency of polymorphisms of selected DNA repair genes in patients with GERD (n=126), BE (n=125) and EADC (n=56) enrolled in a 2-year prospective case-control study. Controls comprised 95 strictly asymptomatic healthy individuals. Using genomic DNA extracted from blood samples, we identified wild-type and polymorphic variants of XPD (Arg156Arg and Lys751Gln), XRCC1 (Arg194Trp and Arg399Gln), XRCC3 (Thr241Met), and the poly (AT) insertion/deletion of XPC (PAT). Allelic frequencies were compared between cases and controls using logistic regression to calculate age, gender, smoking and alcohol-adjusted odds ratios (OR) and 95% confidence intervals (CI). Patients with EADC demonstrated a significantly higher frequency of the XPC PAT homozygous variant genotype compared to asymptomatic controls (OR=3.82; 95% CI=1.05-13.93). Significantly reduced frequencies were seen for the XPD Lys751Gln homozygous variant genotype in patients with EADC (OR=0.24; 95% CI=0.07-0.88), and for the XRCC1 Arg399Gln homozygous variant genotype in patients with BE (OR=0.38; 95% CI=0.12-0.64) and GERD (OR=0.29; 95% CI=0.12-0.66). We conclude that the malignant phenotype probably results from a summation of polymorphic nucleotide excision repair genes showing opposing effects (increased risk for XPC vs. a protective effect for XPD). The protective effect of the homozygous variant of XRCC1 Arg399Gln for GERD and BE suggests that base excision repair alterations may occur early in progression to EADC, likely in response to GERD-induced endogenous oxidative or inflammatory DNA damage. As GERD and BE are highly prevalent in the general population, this protective effect may well explain why only a fraction of individuals with GERD and BE progress to invasive EADC.


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