Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective
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AuthorMolina Zayas, María; Garrido Navas, María del Carmen; García Puche, José Luis; Pedrinaci, Susana; Martínez Atienza, Margarita; García Linares, Susana; Haro Muñoz, Tomás de; Lorente Acosta, José Antonio; Serrano Fernández, María José; Poyatos Andújar, Antonio
Hereditary breast and ovarian cancer (HBOC)BRCA1BRCA2NGSMultigene panel
Molina-Zayas, M... [et al.]. Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective. Mol Genet Genomics (2022). [https://doi.org/10.1007/s00438-022-01891-5]
SponsorshipUniversidad de Granada/CBUA; 2018 AEFA Post-residency Grant (Spanish Association of Clinical Laboratory); Ministry of Economy, Competitiveness, Enterprises and Universities DOC_01682
The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.