Multigene panel testing in Hereditary Breast and Ovarian Cancer: an effective liquid biopsy approach to identify mutations in genes involved in the Homologous Recombination pathway

Background: Hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominant inherited disorder that include 5–7% of all breast cancer (BC) cases and 10-15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 are the most common genes associated to HBOC syndrome. However, hereditary syndrome could be associated with germline PVs in several high- and moderate-risk genes. In recent years, Next-Generation Sequencing (NGS) has allowed to study multiple genes simultaneously, to reduce analysis costs, to led to an explosion of genetic data, and to offer more information to patients. Methods: We retrospectively collected and analyzed to BRCA1/2 test 876 patients affected by BC and OC (531 of BC, 345 of OC) among January 2016 to August 2020. Successively, we analyzed 192 patients resulted BRCA1/2 negative with a strong personal and/or family history to BC and/or OC by using Multi-gene panel testing. We evaluated 22 genes involved in risk of hereditary breast, ovarian and colorectal cancer, and other inherited tumor syndromes. Results: Analysis conducted with multi-gene panel testing revealed that 28 (14.6%) BC and OC patients showed PVs/LPVs in genes no-BRCA. In particular, we analyzed 165 BC patients and 27 OC patients, and we obtained 27 and 4 patients with PVs/LPVs in genes no-BRCA respectively. BC patients with alteration in gene over BRCA hardly showed TNBC than patients with BRCA1/2 or all wt. Moreover, among BC patients with genes altered beyond BRCA the 45.8% showed a Bilateral Breast Cancer. In OC group we observed that 75% of patients with PVs/LPVs in genes over BRCA showed a previously personal history of BC or other cancer. Conclusion: Our analysis showed that the 14.6% of patients BRCA-negative with a strong personal and/or family history to BC and/or OC presented alteration in genes beyond BRCA1/2. This result highlighted the importance of multi-gene panel testing which should be extended at all these patients and be included in clinical practice