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Meta-Analysis
. 2011 Jul;48(7):477-84.
doi: 10.1136/jmedgenet-2011-100018. Epub 2011 May 31.

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

Wei-Yu Lin  1 , Nicola J Camp, Lisa A Cannon-Albright, Kristina Allen-Brady, Sabapathy Balasubramanian, Malcolm W R Reed, John L Hopper, Carmel Apicella, Graham G Giles, Melissa C Southey, Roger L Milne, Jose I Arias-Pérez, Primitiva Menéndez-Rodríguez, Javier Benítez, Magdalena Grundmann, Natalia Dubrowinskaja, Tjoung-Won Park-Simon, Thilo Dörk, Montserrat Garcia-Closas, Jonine Figueroa, Mark Sherman, Jolanta Lissowska, Douglas F Easton, Alison M Dunning, Preetha Rajaraman, Alice J Sigurdson, Michele M Doody, Martha S Linet, Paul D Pharoah, Marjanka K Schmidt, Angela Cox
Affiliations
Meta-Analysis

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

Wei-Yu Lin et al. J Med Genet. 2011 Jul.

Abstract

Background: The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.

Methods: The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% 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 (8074 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), minor allele frequency (MAF)=0.23). This SNP yielded an OR(rec) of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-OR(rec) of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two 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 of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01).

Conclusions: These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.

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Figures

Figure 1
Figure 1
Negative log10 p values for additive, codominant, dominant and recessive models for the XRCC2 SNPs in the SBCS. For each model the upper dash line represents the Bonferroni threshold of 4.2×10−3 and the lower dash line represents the nominal significant value of 0.05. Chromosome positions are given in Mb and refer to NCBI build36/hg18 of the human genome
Figure 2
Figure 2
Meta-analysis of the association of rs3218408 with breast cancer risk. Due to the lack of rs3218408 genotype data in the SEARCH study, data for the highly correlated SNP, rs3218499, was used. Fixed effect estimates are shown, with p value for homogeneity in parenthesis
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