title: Polymorphisms/haplotypes in DNA repair genes and smoking: a bladder cancer case-control study.
abstract: Bladder cancer is associated with tobacco smoking and occupational exposure. The repair of DNA damage has a key role in protecting the genome from the insults of cancer-causing agents. We analyzed 13 polymorphisms in seven DNA repair genes belonging to different repair pathways [X-ray repair cross-complementing group 1 (XRCC1): 26304C>T, 26651A>G, 28152A>G; xeroderma pigmentosum-D (XPD): 23591A>G, 35931A>C; excision repair complementing defective in Chinese hamster, group 1 (ERCC1): 19007C>T; XRCC3: 4541T>C, 17893A>G, 18067C>T; proliferating cell nuclear antigen (PCNA): 6084G>C; ERCC4: 30028C>T, 30147A>G; and XRCC2-31479A>G] in 317 incident bladder cancer patients and 317 controls. After adjustment for age and smoking, the PCNA-6084C variant was significantly associated with an increased risk of bladder cancer [CC + CG versus GG, odds ratio (OR), 1.61; 95% confidence interval (95% CI), 1.00-2.61], as well as the XRCC1-26651G variant (GG+AG versus AA: OR, 1.73; 95% CI, 1.17-2.56). After stratifying by smoking habits, an elevated risk for carriers of the XRCC3-18067T allele was detected both in current (TT versus CC: OR, 2.65; 95% CI, 1.21-5.80; CT versus CC: OR, 1.96; 95% CI, 1.09-3.52) and never smokers (TT versus CC: OR, 4.34; 95% CI, 1.14-16.46; CT versus CC: OR, 2.02; 95% CI, 0.72-5.66), whereas an opposite and slightly weaker effect was associated to the XRCC3-17893G allele in current smokers (GG versus AA: OR, 0.30; 95%CI, 0.11-0.82; AG versus AA: OR, 0.73; 95% CI, 0.42-1.27). XRCC3,XRCC1, ERCC4, and XPD-ERCC1 haplotype frequencies were estimated by the maximum likelihood method. The XRCC3-TAT haplotype was associated with an enhanced risk in the current smokers group (OR, 1.62; 95% CI, 1.15-2.29), whereas a reduction of the risk in the overall sample was observed in the presence of the XRCC3-TAC (OR, 0.69; 95% CI, 0.50-0.97). A significant protective effect of the XPD-ERCC1-ACC haplotype was observed among never smokers (OR, 0.16; 95% CI, 0.03-0.81). Our results suggest that polymorphisms and/or haplotypes in XRCC3, XRCC1, and PCNA genes and spanning XPD-ERCC1 region may modulate bladder cancer risk and that some of these effects may preferentially affect current smokers.
authors.affiliation: Department of Epidemiology and Public Health, Imperial College of Science, Technology and Medicine, Norfolk Place, London W2 1PG, United Kingdom.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.forename: Laura
authors.initials: L
authors.lastname: Davico
authors.forename: Sara
authors.initials: S
authors.lastname: Gamberini
authors.forename: Margaret
authors.initials: M
authors.lastname: Karagas
authors.forename: Giovanni
authors.initials: G
authors.lastname: Casetta
authors.forename: Luigi
authors.initials: L
authors.lastname: Rolle
authors.forename: Alberto
authors.initials: A
authors.lastname: Piazza
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012907:Smoking / Q000009:adverse effects*; D001749:Urinary Bladder Neoplasms / Q000209:etiology* / Q000235:genetics*