Abstract
Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51 to DNA. While germline mutations in RAD51C and RAD51D are associated with high ovarian cancer risk and RAD51B polymorphisms with breast cancer, the contribution of RAD51, XRCC3, and XRCC2 is more unclear. To investigate the role of RAD51, XRCC3, and XRCC2 in breast cancer predisposition and to identify putative recurrent founder mutations in the Finnish population where such mutations have been observed in most of the currently known susceptibility genes, we screened 182 familial Finnish breast or ovarian cancer patients for germline variation in the RAD51and XRCC3 genes and 342 patients for variation in XRCC2, with a subset of the patients selected on the basis of decreased RAD51 protein expression on tumors. We also performed haplotype analyses for 1516 breast cancer cases and 1234 controls to assess the common variation in these genes. No pathogenic mutations were detected in any of the genes and the distribution of haplotypes was similar between cases and controls. Our results suggest that RAD51, XRCC3, and XRCC2 do not substantially contribute to breast cancer predisposition in the Finnish population.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-0880-3) contains supplementary material, which is available to authorized users.
Highlights
Most of the known breast cancer susceptibility genes function in DNA damage repair
Both missenses were predicted to be polymorphisms, tolerated, and neutral by MutationTaster, SIFT, and PON-P, respectively, and both were detected at comparable frequencies (31.3% for rs861539 in XRCC3 and 4.7% for rs3218536 in XRCC2) as in the Finnish population of the 1000Genomes (31.7% for rs861539 and 4.8% for rs3218536) and of the Exome Aggregation Consortium (ExAC) (31.8% for rs861539 and 3.5% for rs3218536) (Exome Aggregation Consortium (ExAC), Cambridge, MA; http://exac.broadinstitute.org [January 2015]), and in the Sequencing Intiative Suomi (SISu) (30.1% for rs861539 and 3.9% for rs3218536)
The association of RAD51, XRCC3, and XRCC2 haplotypes with breast cancer risk was studied among 1516 breast cancer cases and 1234 population controls
Summary
The most important predisposition genes BRCA1 and BRCA2, conferring high life-time risks of breast and ovarian cancer, are involved in the homologous recombination repair (HRR) of DNA double-strand breaks (DSB) (Mavaddat et al 2010). The currently known high, moderate, and low-penetrance alleles together only explain approximately 35% of the familial risk of breast cancer and other susceptibility loci are likely to exist and. Deleterious germline mutations in the XRCC2 gene have been identified in exome sequencing of familial breast cancer patients but the association was not confirmed in a larger case– control study (Park et al 2012; Hilbers et al 2012). Several association studies of XRCC3 have yielded controversial results yet a meta-analysis by He et al
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