Dottorato in MEDICINA MOLECOLARE

Titolo della tesi: Investigating genetic susceptibility to male breast cancer by multigene panel testing: an Italian population-based case-control study

Male breast cancer (MBC) is a rare and understudied disease compared with female breast cancer. A positive family history (FH) of breast cancer (BC) is considered the main risk factor for MBC. About 20% of MBCs have positive BC FH and about 20% of MBCs develop a second tumor other than BC. These data suggest the importance of the genetic component in MBC susceptibility. BRCA1 and BRCA2 are responsible of about 15% of all MBCs. Moreover, recent evidence indicates that PALB2, and possibly other genes, may play a role in MBC susceptibility. Studies are needed to better define the role of these genes and to further explore the missing genetic component in MBC susceptibility. In this context, Next generation sequencing (NGS) technologies offer an unprecedented opportunity for investigating genetic susceptibility as they allow for the evaluation of a large number of genes simultaneously using a multigene panel approach. The aim of this study was to investigate the genetic susceptibility to MBC and estimate MBC risk associated with pathogenic variants in cancer genes other than BRCA1/2. To this end, we performed a population-based case-control study analyzing a large series of Italian MBCs and healthy male controls using a custom multigene panel that included 50 cancer genes; moreover, we compared the main clinical-pathologic characteristics of MBCs with and without pathogenic variants, in order to identify possible distinctive features. A series of 725 MBC negative for BRCA1/2 mutations and 917 male controls, all enrolled in the frame of the Italian multicenter study, were included in the present study. Mutational analysis was performed using NGS technologies by multigene panel approach. All pathogenic variants identified were confirmed by Sanger sequencing. The case-control associations were performed using chi-square test and logistic regression models. Of the 725 MBCs, 36 (5%) were carriers of pathogenic variants in 15 genes and 21 of the 917 healthy male controls (2.3%) were carriers of pathogenic variants in 13 genes. The percentage of pathogenic variants was significantly higher in MBCs compared to male controls (p=0.003). PALB2 was the most common mutated gene. The logistic regression analysis showed that PALB2 pathogenic variant carriers had an approximately 5-fold increased MBC risk (OR: 4.6, 95% CI: 1.00-22.3; p=0.04). Statistically significance difference in the genotype frequency, between cases and control emerged for BLM and FANCM genes (p=0.02, each). The comparison of clinical pathologic characteristics between MBC with and without pathogenic variants showed that MBCs with pathogenic variants had more frequently a positive FH of cancer (p=0.007) and a positive PH of a second tumor other than BC (p=0.02). In conclusion, our data highlight the importance of NGS-based approaches, as multigene panel testing, toward a better comprehension of MBC susceptibility. Our results show that PALB2 may be considered the third MBC susceptibility gene, after BRCA1/2, in the Italian population. Overall, our findings may guide the management of MBC patients, particularly those with family and personal history of multiple cancer, and eventually their relatives, in terms of cancer surveillance and screening.