The role of variants of homologous recombination repair genes in breast cancer susceptibility and DNA repair

Apart from being the most common malignancy in women worldwide, breast cancer is also one of the most extensively investigated human cancers. The breast cancer susceptibility genes, BRCA1 and BRCA2 are responsible for less than 10% of breast cancer cases. However the genetic basis of the majority of breast cancer has not yet been identified. Since an acquired genetic instability resulting from the defects in DNA repair is known to promote tumorigenesis, a proportion of inherited breast cancers might be attributable to mutations in the genes involved in these functions. Homologous Recombination Repair (HRR) is an accurate and high fidelity repair mechanism, which is mainly responsible for repair of DNA double strand breaks (DSBs). There is considerable evidence to suggest that defects in DNA damage repair in particular in HRR contribute to breast cancer. In the present study we tested the effect of single nucleotide polymorphisms of HRR genes on breast cancer susceptibility. We screened a series of 522 breast cancer patients and 900 healthy controls for a panel of four polymorphic HRR genes. The rare allele of XRCC2 R188H was found to be associated with increased risk of breast cancer (odds ratio: 1.32, CI: 0.98,1.79). This allele was also shown to be more associated with lobular breast carcinoma (p=0.001). Furthermore there was preliminary evidence of interaction between XRCC2 R188H and XRCC3 T241 M, and also between XRCC3 T241 M and BRCA2 N372H alleles (both p=0.06). Four novel naturally occurring sequence variants of the XRCC3 DNA repair gene were also identified. We studied the effect of these sequence variants on the repair ability of the XRCC3 protein. A rare XRCC3 variant (D213N), was shown to completely ablate the protein function. The association of this variant with cancer susceptibility was studied in a group of 1524 patients with common cancer and 1577 healthy individuals. However, no association between this variant and cancer susceptibility was found, indicating that XRCC3 is unlikely to be a tumour suppressor gene. The results from the present study support the hypothesis that normally occurring variation in DNA repair genes can influence DNA repair capacity and cancer susceptibility in the population.