Identification of a <i>BRCA2</i>-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

<div><p>Common genetic variants contribute to the observed variation in breast cancer risk for <i>BRCA2</i> mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for <i>BRCA2</i> mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected <i>BRCA2</i> mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of <i>BRCA1/2</i> were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these <i>BRCA2</i> mutation carriers and for several regions (including <i>FGFR2</i>, <i>MAP3K1</i>, <i>CDKN2A/B</i>, and <i>PTHLH</i>) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in <i>BRCA2</i> mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10⁻⁸). This SNP was not associated with breast cancer risk either in the general population or in <i>BRCA1</i> mutation carriers. The locus lies within a region containing <i>TFAP2A</i>, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a <i>BRCA2</i> mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in <i>BRCA2</i> mutation carriers. This panel may have clinical utility for women with <i>BRCA2</i> mutations weighing options for medical prevention of breast cancer.</p>