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

Abstract

Individuals differ widely in their ability to repair DNA damage, and DNA‐repair deficiency may be involved in modulating cancer risk. In a case‐control 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‐Lys751Gln, exon 23) have been analyzed. Results were correlated with DNA damage measured as ³²P‐post‐labeling bulky DNA adducts in white blood cells from peripheral blood. Genotyping was performed by PCR‐RFLP analysis, and allele frequencies in cases/controls were as follows: XRCC1‐399Gln = 0.34/0.39, XRCC3‐241Met = 0.48/0.35 and XPD‐751Gln = 0.42/0.42. Odds ratios (ORs) were significantly greater than 1 only for the XRCC3 (exon 7) variant, and they were consistent across the 2 control groups. XPD and XRCC1 appear to have 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 adduct levels above the median was higher in NAT‐2 slow acetylators, homozygotes for the XRCC3‐241Met variant allele (OR = 14.6, 95% CI 1.5–138). However, any discussion of interactions should be considered preliminary because of the small numbers involved. Our results suggest that bladder‐cancer risk can be genetically modulated by XRCC3, which may repair DNA cross‐link lesions produced by aromatic amines and other environmental chemicals.