DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study

Individuals differ widely in their ability to repair DNA damage, and DNA-re pair deficiency may be involved in modulating cancer risk, In a case-contro l study of 124 bladder-cancer patients and 85 hospital controls (urological and non-urological), 3 DNA polymorphisms localized in 3 genes of different repair pathways (XRCC1-Arg399Gln, exon 10; XRCC3-Thr241Met, exon 7; XPD-Ly s751Gln, exon 23) have been analyzed. Results were correlated with DNA dama ge measured as P-32-post-labeling bulky DNA adducts in white blood cells fr om peripheral blood, Genotyping was performed by PCR-RFLP analysis, and all ele frequencies in cases/controls were as follows: XRCC1-399Gln = 0.34/0.39 , XRCC3-241 Met = 0.48/0.35 and XPD-751Gln = 0.42/0.42. Odds ratios (ORs) w ere significantly greater than 1 only for the XRCC3 (exon 7) variant, and t hey were consistent across the 2 control groups, XPD and XRCC1 appear to ha ve no impact on the risk of bladder cancer, Indeed, the effect of XRCC3 was more evident in non-smokers [OR = 4.8, 95% confidence interval (CI) 1.1-21 .2]. XRCC3 apparently interacted with the N-acetyltransferase type 2 (NAT 2 ) genotype. The effect of XRCC3 was limited to the NAT-2 slow genotype (OR = 3.4, 95% CI 1.5-7.9), suggesting that XRCC3 might be involved in a common repair pathway of bulky DNA adducts, In addition, the risk of having DNA a dduct levels above the median was higher in NAT-2 slow acetylators, homozyg otes for the XRCC3-241Met variant allele (OR = 14.6, 95% CI 1.5-138). Howev er, any discussion of interactions should be considered preliminary because of the small numbers involved. Our results suggest that bladder-cancer ris k can be genetically modulated by XRCC3, which may repair DNA cross-link le sions produced by aromatic amines and other environmental chemicals. (C) 20 01 Wiley-Liss, Inc.