Titolo della tesi: Molecular Characterization of the Hereditary Breast Cancer from BRCA1 and BRCA2 genes analysis to multi-gene panels
The 5-10% of breast/ovarian cancers (BC and OC) are inherited, and germline patho-genic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10-20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogen-ic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype.A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classi-fied as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereasand a VUS was identified in 20% of the probands. We observed a high incidence of deleterious vari-ants in theCHEK2 gene and a new pathogenic variant was detected in the RECQL gene. These results support the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.