Carcinogenesis Advance Access originally published online on January 29, 2007
Carcinogenesis 2007 28(6):1254-1258; 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, USA
2 Occupational Health Program, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA
3 Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Room 7-124, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada
4 Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
5 Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +1 416 946 4501 ext. 3428; Fax: +1 416 946 6546; Email: 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, xeroderma pigmentosum group D (XPD) (Asp312Asn and Lys751Gln) in the nucleotide excision repair (NER) pathway and X-ray repair cross-complementing gene 1 (XRCC1) (Arg399Gln) in the base excision repair (BER) 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 (ORs) and 95% confidence intervals (CIs) were obtained from logistic regression models, adjusted for body mass index at 18 years of age, 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 with 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 ORs 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 NER and BER pathways are important to the development of EA.
Abbreviations: AOR, adjusted odds ratio; BER, base excision repair; BMI, body mass index; CI, confidence interval; EA, esophageal adenocarcinoma; GERD, gastroesophageal reflux disease; NER, nucleotide excision repair; OR, odds ratio; XPD, xeroderma pigmentosum group D; XRCC1, X-ray repair cross-complementing gene 1
Received December 1, 2006; revised December 31, 2006; accepted January 16, 2007.
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