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

Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 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 BRCA2 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 BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) 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 BRCA2 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 BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, 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 BRCA2 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 BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers

“…Genotypes at many millions of common variants across the genome can be genotyped or imputed with high accuracy using largescale genotyping arrays, using reference panels from the 1000 Genomes Project (Auton et al 2015). This approach has been applied with great success in cancer epidemiology in the general population, with GWAS having identified more than 100 common susceptibility variants for breast cancer , Hunter et al 2007, Stacey et al 2007, Ahmed et al 2009, Thomas et al 2009, Antoniou et al 2010b, Turnbull et al 2010, Cai et al 2011, Fletcher et al 2011, Ghoussaini et al 2012, Hein et al 2012, Long et al 2012, Siddiq et al 2012, Bojesen et al 2013, French et al 2013, Garcia-Closas et al 2013, Gaudet et al 2013, Meyer et al 2013, Cai et al 2014, Milne et al 2014a, Orr et al 2015, Couch et al 2016, Dunning et al 2016, Lawrenson et al 2016, Zheng et al 2009) and 22 for ovarian cancer (Song et al 2009, Bolton et al 2010, Goode et al 2010, Bojesen et al 2013, Permuth-Wey et al 2013, Pharoah et al 2013, Kuchenbaecker et al 2015.…”

“…In this context, within CIMBA, four approaches have been applied to identify loci associated with breast and ovarian cancer for mutation carriers: (i) GWAS for breast and ovarian cancer specifically performed in samples of BRCA1 and BRCA2 mutation carriers (Antoniou et al 2010b, Gaudet et al 2013; (ii) association 23:10 studies to assess common breast and ovarian cancer susceptibility alleles identified in the general population as potential modifiers of risk for mutation carriers (Antoniou et al 2008b, Kuchenbaecker et al 2014; (iii) meta-analyses of GWAS performed in BRCA1 and BRCA2 mutation carriers with GWAS of related phenotypes in the general population (for example, combining studies of breast cancer risk for BRCA1 mutation carriers with those of oestrogen receptor-negative breast cancer in general population or studies of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers with GWAS of serous ovarian cancer in the general population) (Kuchenbaecker et al 2015, Couch et al 2016; and iv) finescale mapping of risk-modifying loci identified through GWAS approaches to fully characterise the associations with all genetic variants at these loci (Bojesen et al 2013, Dunning et al 2016, Lawrenson et al 2016.…”

“…The second implication informs approach (iii) above, and is that an optimal strategy for the identification of novel genetic modifiers is meta-analysis of GWAS of these related phenotypes (Kuchenbaecker et al 2015, Couch et al 2016. Nevertheless, there appear to be some loci that modify breast or ovarian cancer risk specifically for BRCA1 and BRCA2 mutation carriers, showing no evidence of association with risk in the general population , Gaudet et al 2013. As summarised in Table 1, to date, a total of 26 and 16 single nucleotide polymorphisms (SNPs) associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, respectively, have been identified.…”

“…The associated effect sizes are small, with estimated relative risks per copy of the minor allele in the range 1.05-1.26 for breast cancer and 1.03-1.48 for ovarian cancer. These genetic modifiers are estimated to account for a relatively small proportion (<10%) of the modifying genetic variance for BRCA1 and BRCA2 mutation carriers (based on estimates of the modifying variance from segregation analyses), and it is predicted that residual family history remains an important risk-modifying factor , Gaudet et al 2013, Kuchenbaecker et al 2015, as recently demonstrated in the general population (Mavaddat et al 2015). However, the joint effects of SNPs and family history have not been estimated for BRCA1 and BRCA2 mutation carriers.…”

“…*Classical genome-wide statistical significance; # Nominal statistical significance, given the high prior probability of association based on evidence (at P < 5 × 10 −8 ) from other GWAS; † Genome-wide statistical significance in meta-analysis and HR estimate consistent in direction with findings for non-carriers; ‡ Statistical significance assessed in mutation carriers after adjustment for the top hit(s). a Antoniou et al (2010b); b Couch et al (2013); c Gaudet et al (2013); d Antoniou et al (2012) …”