Carcinogenesis Advance Access published online on January 29, 2007
Carcinogenesis, doi:10.1093/carcin/bgm020
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XRCC1 and XPD Polymorphisms and Esophageal Adenocarcinoma Risk
1 Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114
4 Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114
3 Ontario Cancer Institute/Princess Margaret Hospital, Toronto, 610 University Avenue, Toronto, ON, M5G 2M9
2 Occupational Health Program, Harvard School of Public Health, 665 Huntington Ave, Boston, MA, 02115
5 Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts, 02115
Requests for reprints: Dr. Geoffrey Liu, Ontario Cancer Institute/Princess Margaret Hospital, Room 7-124, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada. Geoffrey.Liu{at}uhn.on.ca
DNA damage is important in the pathogenesis of esophageal adenocarcinoma (EA). Polymorphic variants in DNA repair genes may be modifiers of the risk of EA through their role in altering human host response to gastroesophageal acid reflux, a well-described risk factor for EA. We studied the role of genetic polymorphisms of two key DNA repair genes, XPD (Asp312Asn and Lys751Gln) in the nucleotide excision repair pathway and XRCC1 (Arg399Gln) in the base excision repair pathway, in the development of EA in 183 cases and 336 frequency-matched controls for age, gender and race. Genomic DNA was extracted from blood samples. Odds ratios (OR) and 95% confidence intervals were obtained from logistic regression models, adjusted for body mass index at age 18 years, smoking, and alcohol exposure. The variant genotypes of XPD Lys751Gln polymorphism were associated with a higher risk of EA: the adjusted OR comparing Gln/Gln+Lys/Gln to Lys/Lys was 1.49 (95%CI:1.02-2.14). Although no significant relationships were found for the XRCC1 Arg399Gln polymorphism alone, this polymorphism did modify the relationship between XPD Lys751Gln and EA risk: when both polymorphisms were evaluated together, adding the number of variant alleles of the two polymorphisms resulted in a significant trend (trend test,p=0.008): compared with individuals with no variant alleles (n=88), the adjusted OR of developing EA are 1.49 (95%CI:0.88-2.59), 1.69 (95%CI:0.98-2.96) and 2.58 (95%CI:1.31-5.06) for one (n=195), two (n=166), and three or four variant alleles (n=70), respectively. No relationships were found for the XPD Asp312Asn polymorphism. We conclude that combined nucleotide and base excision repair pathways are important to the development of EA.
Key Words: DNA repair gene • XRCC1 • XPD • polymorphisms • esophageal cancer • adenocarcinoma
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