XRCC3 polymorphisms and risk of lung cancer

In a nested case-cohort study, we have investigated the occurrence of lung cancer in relation to polymorphisms in the double strand DNA repair gene XRCC3. Among 54,220 members of a Danish prospective cohort study aged 50-65 at entry, 265 lung cancer cases were identified and a sub-cohort, matched by age, sex and duration of smoking, comprising of 272 individuals was used for comparison. Ninety percent of both cases and comparison group were ever-smokers. Three previously studied polymorphisms; XRCC3 A4541G (5'UTR), A17893G (IVS5-14) and C18067T (T241M) were combined into haplotypes. The four most frequent haplotypes accounted for 98% of the genotypes. Homozygosity for the haplotype AAC was associated with a 4.91 times higher risk of lung cancer (confidence interval, 95% CI = 1.06-22.81) compared with the GAC haplotype. The polymorphism XRCC3 IVS6 C1571T was found to co-segregate with the AAC haplotype, and homozygous carriers of the variant T-allele had a 4.47 (CI = 1.34-14.96) times higher risk of lung cancer compared with homozygous carriers of the wild type allele. Our results indicate that XRCC3 IVS6 C1571T and the associated haplotype AAC are associated with relatively high risk of lung cancer.