Genetic landscape in HBOC families from Brazil: A mutational analysis

Background: Even if 10% of breast cancers are diagnosed in the context of hereditary predisposition, for a great proportion of families the molecular mechanism of cancer predisposition remains unclear. Founder mutations with increased risk for breast and other cancers have been described in some latin American countries, but the hereditary breast and ovarian cancer (HBOC) mutational landscape remains understudied in this population of highly mixed genetic contributions. Our study aims to evaluate the contribution of germline BRCA1/2 and moderated penetrance genes mutations in the incidence of HBOC brazilian families. Methods: This is a retrospective analysis of a series of 666 consecutive patients with HBOC syndrome who underwent genetic test between March 2007 and March 2017 in Sirio-Libanes Hospital. Clinical, pathological and sequencing available data on mutations and unclassified variants in high, moderate and low penetrance genes was analysed. Results: The majority of the patients were tested in the context of multigene NGS pannels (69%), 205 of the patients had only access to BRCA1/2 full gene screening. A pathogenic mutation was identified in 227 index cases (34%). Unclassified variants (UV) were present in 139 tests (19%). BRCA1/2 mutations could explain the molecular mechanism of cancer predisposition of 133 cases (20%) while TP53 gene was the second most commonly mutated gene in our cohort (46 patients, 7%). 83% of TP53 mutation corresponded to the brazilian TP53 founder mutation R337H (c.1010G>A). Intermediate penetrance genes mutations were present in 22 cases (3,3%): 11 for PALB2, 6 for ATM, 4 for CHEK1, 1 for BRIP1. Mismatch repair genes were mutated in 3% of the patients. The index cases were in majority women (98%) diagnosed with breast cancer under 50 years (34%), 68 (10%) of them with bilateral breast tumors.Table1420PGenePathogenic mutations (n)UVBRCA19017BRCA24339TP53466PTEN01CDH106STK1100PALB2115ATM613BRIP125CHEK2410RAD51C13BARD123BAP103MLH187MSH276PMS256MSH6011EPCAM00BMPR100 Open table in a new tab Conclusions: For the majority of the patients the mechanism of predisposition remains unknown. All together BRCA1, BRCA2 and TP53 mutations could explain the predisposition of 27% of the index cases in our cohort. Legal entity responsible for the study: Registro de Câncer Hereditário Brasileiro Funding: None Disclosure: All authors have declared no conflicts of interest.