Dottorato in BIOLOGIA UMANA E GENETICA MEDICA

Titolo della tesi: DNA repair genes in cancer predisposition: detection of germline pathogenic variants by multigene panel testing

The 5 to 10% diagnosed cancers are linked to an inherited faulty gene. Mutations in distinct DNA repair systems elevate the susceptibility to various cancer types and germline pathogenic (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 of Breast, Ovarian, colorectal and endometrial cancer, but the prevalence of pathogenic variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 416 patients (298 cases were non-BRCA) was analyzed by next-generation sequencing using a multigene panel of the 28 DDR pathways genes related to Breast, Ovarian, colorectal and endometrial cancer. 41 of 416 affected individual were diagnosed with Lynch syndrome. 213 unique variants in 27 of 28 analyzed genes were found, 37 classified as likely pathogenic/ pathogenic and 177 as variants of un-known significance. 10 of 37 LP/P variants were discovered in 10 patients with Lynch syndrome. It was observed a high incidence of deleterious variants in the ATM, MUTYH, CHEK2 and MSH6 genes. These results support the clinical utility of multigene panel to in-crease the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches. Keywords: Cancer; Lynch syndrome; DDR; BRCA1/2; HBOC