Abstract A75: DNA repair genotypes associated with benign breast disease in women at high breast cancer risk

Benign breast disease (BBD) is a risk factor for breast cancer and may have a heritable component. Little is known about genetic factors associated with BBD risk. Deficient DNA repair has been implicated in the etiology of breast cancer. Since DNA repair occurs early in the breast carcinogenesis pathway, it is logical that polymorphic forms of DNA repair genes may alter BBD risk. No prior studies have reported on the association between DNA repair variants and BBD.

We examined the association between a panel of DNA repair genotypes and BBD in a sub-cohort of women within CLUE II, a population based cohort study in Washington County, Maryland. The women were followed from 1989 to 2003 with biennial questionnaires from 1996 onwards eliciting information on many health outcomes, including physician diagnosis of BBD and breast biopsies. 3,212 women reporting no prior diagnosis of BBD at baseline were genotyped for non-synonymous SNPs in 8 DNA repair genes (ERCC2, ERCC4, ERCC5, RAD23B, XPC, XRCC1, XRCC2, and XRCC4) that had previously been implicated in cancer risk. BBD-free survival time was fitted to age-adjusted Cox proportional hazards model and analyzed by DNA repair genotype.

Carriers of the variant alleles of XRCC1 codon 194 and ERCC4 codon 415 were significantly more likely to be diagnosed with BBD than non-carriers -- hazard ratios (HR) = 1.36, 95%CI 1.06-1.74 and 1.39, 95%CI 1.09-1.76, respectively. The association between the ERCC4 variant and BBD was even greater among women with a positive family history of breast cancer. In this subgroup, the variant ERCC4 allele was associated with a 2.7 fold increase in breast cancer risk (HR = 2.63, 95% CI 1.52-4.66, p interaction = 0.02).

Variant ERCC4 and XRCC1 genotypes are significantly associated with a diagnosis of BBD in this population, particularly in women with a family history of breast cancer. These same genes have also been implicated in the risk of breast cancer in other studies. Taken together, these studies support the notion that these two DNA repair genes may have a common role in the etiology of both BBD and breast cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A75.