IDENTIFICATION OF GERMLINE VARIANTS AND FAMILY HISTORY CHARACTERIZATION IN NON-BRCA MALE BREAST CANCER BRAZILIAN CASES

Although breast cancer is the most common tumor type among women, in men it represents about 1% of all cancers identified. There are very few studies related to the genetic causes associated with male breast cancer (MBC). Considering the importance of genetics in the adoption of personalized preventive and treatment strategies, this study aimed to identify novel MBC predisposition genes through whole-exome sequencing, that could have an impact on the identification, treatment and follow up of men with a breast cancer diagnosis. A total of 30 unrelated Brazilian men with breast cancer, BRCA1/BRCA2 wild-type (WT) and unselected for family history were included in the study. The median age of cancer diagnosis was 54 years (32 – 78; SD: 12.13), and family history (FH) of cancer was reported by 86.7% of the participants, with 12 reporting breast cancer cases in the family (two of them have other MBC cases in first-degree relatives). In total, 278 unique germline variants were identified (excluding benign/likely benign). Overall 19% (53 of 278) of the variants identified occurred in DNA damage repair genes. Genes present in other carcinogenesis-related pathways were 74.1% (206 of 278). The presence of Pathogenic/Likely Pathogenic (P/LP) variants was identified in 33.3% of the cases (10/30). Among the P/LP variants, 21.4% of them affected known cancer predisposition genes, such as BRIP1, MSH6 and MUTYH, as well as, BRIP1, ERCC2, MSH6, MRE11 and MUTYH (35.7%) were involved in DNA repair pathways. These findings may be even more important for men with P/LP variants in genes present in pathways that already have therapeutic targets, such as the use of PARP inhibitors (iPARP). This approach proved to be efficient for patients with P/LP variants in BRCA1/2, genes involved in the DNA double-strand break (DSB) repair pathway, and is already used in clinical practice. This treatment has also been tested in patients with variants in other genes involved in this pathway. Thus, the cases in our cohort in which variants were identified in the BRIP1 and MRE11 genes could benefit from the use of iPARP. Ultimately, this is the first study with Brazilian familial male breast cancer cases and contributes to increasing our knowledge of the genetics of MBC.