Abstract
The 5–10% of breast/ovarian cancers (BC and OC) are inherited, 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 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 pathogenic 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 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported 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.
Highlights
Hereditary breast, ovarian, and pancreatic cancers are associated with the presence of germline pathogenic (P) or likely pathogenic (LP) variants in the BRCA1 and BRCA2 genes
In 16/113 BRCA1/2-negative index cases (14%), we identified LP/P variants, whereas 23 probands were the carrier of variants of uncertain significance (VUS) (20%)
Six were detected in the CHEK2 gene, three in RAD51C, two in ATM, while single variants P/LP were detected in RECQL, MLH1, and MSH2 genes
Summary
Hereditary breast, ovarian, and pancreatic cancers are associated with the presence of germline pathogenic (P) or likely pathogenic (LP) variants in the BRCA1 and BRCA2 genes. As the remaining 80% is still waiting for genetic diagnosis, the discovery of new genes involved in the susceptibility of hereditary cancers is under continuous investigation. The identification of pathogenic variants in other genes at both a germline and somatic is, crucial for the future of primary prevention strategies (prophylactic surgery and drug-prevention), surveillance programs, and targeted therapy. In this scenario, the research of hereditary breast/ovarian cancer susceptibility genes is crucial. BRCA1/2 have been primarily investigated for diagnostic purposes because their mutations show high penetrance, conferring the 5-fold higher risk of breast cancer in P/LP variant carriers compared to the general population [2]
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