A role for XRCC4 in age at diagnosis and breast cancer risk.

Genetic variants in DNA repair genes influence the ability to repair damaged DNA. Unrepaired or improperly repaired DNA may lead to genetic instability and carcinogenesis. We evaluated the role of four tagging single nucleotide polymorphisms (tSNP) in the DNA repair gene, XRCC4, and its association with breast cancer risk and age at diagnosis of breast cancer in 464 cases and 576 controls selected to be BRCA1/2 mutation negative from high-risk Utah pedigrees. We observed a significant association for two 4-locus tSNP haplotypes and age at diagnosis. Carriage of one haplotype was associated with later diagnosis (haplotype frequency, 0.039; mean age at diagnosis, 67.17 years; P = 0.001), and carriage of the other was associated with earlier diagnosis (haplotype frequency, 0.214; mean age at diagnosis, 54.04 years; P = 0.0085). For breast cancer risk, two 2-locus tSNP haplotypes explained the observed association as well as extended four-locus haplotypes. The two 2-locus haplotypes were nominally associated with breast cancer risk, one for reduced risk (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = 0.014) and one for increased risk (odds ratio, 1.30; 95% confidence interval, 1.02-1.67; P = 0.033). Moreover, one of the tSNPs is in strong linkage disequilibrium (D' = 1.00) with an XRCC4 SNP found to be significantly associated with breast cancer risk in Taiwan, hence, confirming their findings. Our results suggest that XRCC4 may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases.