733 Common Breast Cancer Susceptibility Alleles in BRCA-positive and BRCA-negative Male Breast Cancer

Background: Over the last 4 years, common low-penetrance breast cancer (BC) susceptibility alleles have been reported in a total of 24 loci, identified through GWAS or candidate gene approach. Interestingly, SNPs in these loci seem also to be associated with particular clinical-pathologic features of BC, such as hormonal receptors status, and BRCA1/2 mutational status. Recently, an involvement of low-penetrance alleles in male BC (MBC) susceptibility has been suggested, however, whether these loci are associated with clinical-pathologic features of MBC or BRCA1/2 mutational status is still largely unknown. Our aim was to evaluate the impact of 8 selected lowpenetrance alleles in MBC susceptibility, and to assess associations between BC susceptibility alleles and clinical-pathologic features of MBC, including BRCA1/2 mutational status. Material and Methods: A case-control study was performed on a large MBC series collected in the first Italian multicentre study on MBC. A total of 395 MBC cases, including 46 BRCA1/2 mutation carriers, together with their clinicalpathologic characteristics, and 847 male controls, including 124 unaffected BRCA1/2 mutation carriers, were genotyped by allelic-discrimination realtime PCR with TaqMan probes at FGFR2 rs2981582, TNRC9 rs3803662, MAP3K1 rs889312, LSP1 rs3817198, 2q35 rs13387042, ESR1 rs2046210, 5p12 rs10941679 and CASP8 rs1045485. Results: We found the greatest associations with overall MBC risk for SNPs at FGFR2 (per allele OR, 1.21; 95% CI, 1.02–1.44), TNRC9 (per allele OR, 1.50; 95% CI, 1.26–1.78) and ESR1 (per allele OR, 1.67; 95% CI, 1.41–1.98). Statistically significant associations (p < 0.05) emerged between FGFR2 and TNRC9 minor alleles and BRCA2-negative MBCs, and between ESR1 minor allele and BRCA2-positive MBCs. ESR1 was indeed associated with PR−, HER2+, higher tumor grade and BC family history, whereas FGFR2 and TNRC9 were associated with PR+, HER2−, lower tumor grade and absence of BC family history. Conclusions: Overall, based on a large multicentre series, our data support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility. Moreover, our results suggest that specific loci may be associated with distinct MBC subtypes and may act as genetic modifiers of BRCA2 in men. Study supported by AIRC (IG 8713)