A role for XRCC2 gene polymorphisms in breast cancer risk and survival

Abstract

Background The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. We hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer. Methods We genotyped 12 XRCC2 tagging SNPs in 1,131 breast cancer cases and 1,148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating odds ratios (ORs) and hazard ratios (HRs), and their corresponding 95% confidence intervals (CIs). Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8,074 cases) from the Breast Cancer Association Consortium (BCAC). Results The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10−4, MAF=0.23). This SNP yielded an ORrec (95% CI) of 1.64 (1.25–2.16) in a two-site analysis of SBCS and UBCS, and a meta-ORrec (95% CI) of 1.33 (1.12–1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by 2 in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR (95% CI) of 1.58 (1.01–2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8,781 breast cancer patients from the BCAC [HR (95% CI) of 1.19 (1.05–1.36), p=0.01]. Conclusions Our findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.

Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer

“…There was no significant difference in the mean age at diagnosis between non-carriers and the carriers of the p.N457K haplotype (57.0 versus 56.7 years, respectively). Because some SNPs in double-strand break repair genes may impinge on prognosis rather than risk [25,26], we also assessed whether the rs74319927 haplotype could affect survival from breast cancer. In the 829 patients for whom follow-up data 21 22 22 22 22 22 22 22 22 22 22 22 22 22 21 22 21 22 (0.10) During the resequencing study, a total of four new missense substitutions were identified in the coding region, each of them in a single case (Fig.…”

“…The HaBCS includes a hospital-based series of 1012 unselected German breast cancer patients who were treated at the Department of Radiation Oncology at Hannover Medical School from 1996 to 2001. This patient series had been used previously to determine the frequency [17][18][19][20], to study some more common polymorphisms in candidate genes by the Breast Cancer Association Consortium [21][22][23][24] or for collaborative survival analyses [25,26]. Genomic DNA was available for 965 patients, and follow-up data were available for 829 patients, with a median follow-up time of 7.6 years.…”

Association between -41657C/T single nucleotide polymorphism of DNA repair gene XRCC2 and endometrial cancer risk in Polish women

“…Moreover, it has been proven that polymorphisms in XRCC2 may modify individual susceptibility to various types of cancer [6][7][8][9][10][11][12][13].…”

Germline DNA Variations in Breast Cancer Predisposition and Prognosis: A Systematic Review of the Literature

“…In candidate gene association studies, SNPs in or close to candidate genes are examined for their roles in breast cancer predisposition, governed by a hypothesisdriven approach. Several candidate gene association studies for breast cancer have been conducted during the last 10 years [Allen-Brady et al, 2006;Bewick et al, 2006;Haiman et al, 2008;Pooley et al, 2008;Sehl et al, 2009;Lin et al, 2011;Mangoni et al, 2011]; however, many of these studies were underpowered due to small sample size, resulting in inconsistent and irreproducible findings [Dunning et al, 1999;Pharoah et al, 2002]. To date, only 1 SNP (rs1045485) located in the coding region of CASP8 identified by a candidate gene association study has shown promise as a breast cancer predisposition risk factor .…”

“…Initial genetic association studies for breast cancer were focused on interrogating a handful of SNPs in candidate genes or pathways such as DNA repair, apoptosis and cell-cycle checkpoints [Allen-Brady et al, 2006;Bewick et al, 2006;Mitra et al, 2008;Sehl et al, 2009;Economopoulos and Sergentanis, 2010;Lin et al, 2011;Mangoni et al, 2011]. Earlier this decade, completion of the Human Genome Project and the International HapMap Project, coupled with advances in genotyping technologies, made it possible to analyze the whole genome for SNPs associated with complex traits.…”