961: Low-penetrance alleles and male breast cancer risk: Results from a multicenter study in Italy

Background: Breast cancer (BC) in men is a rare disease. About 15% of male BCs (MBCs) are due to mutations in the high-penetrance BC genes, BRCA1 and BRCA2. Recently, common genetic variants have been shown to contribute to the heritable risk of MBC. In previous studies, we showed that RAD51B rs1314913 is specifically associated with BC risk in men, and that ESR1 rs2046210 is associated with ER negative status and BRCA1/2 mutations in MBC. Here, we investigated whether single nucleotide polymorphisms (SNPs) in the multi-cancer susceptibility 8q24 region and in other BC-associated regions may influence MBC risk in Italian population, and whether these variants may be associated with specific clinical-pathologic features of MBC. Material and Methods: A case–control study was performed on 387 MBC cases and 908 healthy male controls. The MBC series included 50 BRCA1/2 mutation carriers. An additional series of 197 healthy male BRCA1/2 mutation carriers was collected in order to compare affected and unaffected male carriers. All samples were genotyped by iPLEX technology on Sequenom MassARRAY platform for a total of 30 susceptibility SNPs within chromosomes 9, 10, 11, 12, 12, 14, 21, and 8q24 region. Analyses were performed by logistic regression models, adjusted for age and center of enrolment. Results: We found a significant association with MBC risk for five SNPs including 8q24.21/rs445114 (OR = 1.57, 95% CI: 1.05–2.34; p = 0.026), 8q24.21/rs1562430 (OR = 0.52, 95% CI: 0.34–0.79; p = 0.002), 9p21.3/ rs1011970 (OR = 2.38, 95% CI: 1.22–4.64; p = 0.011), 11q13.3/rs614367 (OR = 2.57, 95% CI: 1.19–5.54; p = 0.016), and 14q24.1/rs1314913 (OR = 3.10, 95% CI: 1.84–5.22; p < 0.0001). By stepwise approach, 8q24.21/rs1562430 and 14q24.1/rs1314913 emerged as the SNPs more strongly associated with MBC risk. Significant associations of rs614367/11q13 genotypes with ER status (p = 0.006), and of 9p21.3/rs1011970 genotypes with HER2 status (p = 0.002) emerged. Notably, rs1314913/RAD51B was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (OR = 1.69; 95% CI: 1.02–2.78; p = 0.04). Conclusions: We provided the first evidence that the 8q24 multicancer susceptibility region is associated with MBC risk. Moreover, we suggested a role for the MBC-specific SNP rs1314913/RAD51B as risk modifier locus in BRCA1/2 male carriers. Overall, the present findings, in combination with our previous results, add to the accumulating evidence that common low-penetrance susceptibility alleles play a relevant role in MBC susceptibility. Study supported by AIRC (IG12780) to L.O. and FIRC (triennial fellowship ‘Mario e Valeria Rindi’) to V.S. No conflict of interest.