hereditary breast and ovarian cancer; HBOC; Brazilian population; next-generation sequencing

Hereditary breast and ovarian cancer syndrome (HBOC) accounts for 5-10% of all breast cancer cases. Although the genes most commonly associated with the syndrome are BRCA1 and BRCA2, several other genes have been described and, when mutated, increase the risk of developing the disease. With next-generation sequencing (NGS) it is possible to analyze multiple genes and better identify individuals at high risk of breast and/or ovarian cancer. To date, no study has performed sequencing involving a multigene panel in patients with clinical criteria for HBOC in the population of Minas Gerais. Therefore, the aim of this study was to carry out a detailed literature review to understand the molecular profile related to HBOC in Brazil and subsequently to track and evaluate, by NGS, several genes predisposing to the syndrome in Minas Gerais. For this, a panel for sequencing on the Illumina MiSeq® platform composed of 22 genes was customized. One hundred and four patients with breast and/or ovarian cancer treated at the Hospital do Câncer in the city of Divinópolis met the clinical criteria of the National Comprehensive Cancer Network (NCCN) for HBOC, of which 72 were interested and were referred for genetic testing. Among the 72 patients evaluated, 50% were classified as “Patient whose age at diagnosis of breast cancer is less than 45 years old” or “Patient < 50 years old with one or more family members with breast, ovarian, pancreas and/or prostate cancer in any age”, these being the two most frequently encountered criteria.

Pathogenic or probably pathogenic mutations were identified in 22.22% (16/72) of patients, with 9.72% (7/72) having mutations in BRCA1/2 genes and 12.50% (9/72) having mutations in non-BRCA genes (ATM, CHEK2, PALB2, MSH2, RAD51C and TP53). Altogether 10 different mutations of uncertain significance (VUS) were found, of which the majority, 5.56% (4/72), were identified in the ATM gene. The most frequently found pathogenic variant was p.R337H (c.1010G>A) in the TP53 gene. Considering data from the literature review, the frequency of the p.R337H mutation in HBOC patients in Brazil was estimated at 1.83% (61/3336). The RAD51C gene presented in this study a high frequency of mutations in patients with criteria for HBOC, 2.78% (2/72), in relation to other Brazilian studies. Interestingly, the second most mutated non-BRCA gene in Brazil, according to data from the literature review, was MUTYH. However, the MUTYH gene was not included in the panel design of this work and will be evaluated in future studies.