• Ana Rafaela de Souza Timoteo, Ana Élida Menezes Magalhães Gonçalves, Lucas Amadeus Porpino Sales, Betina Menezes Albuquerque, Jorge Estefano Santana de Souza, Patrícia Cristina Pascoto de Moura, Marcos Alberto Arruda de Aquino, Lucymara Fassarela Agnez-Lima, and Tirzah Braz Petta Lajus.
• Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, Av. Senador Salgado Filho, s/n, Natal, 59078-970, Brazil.
• Breast Cancer Res. Treat. 2018 Dec 1; 172 (3): 637-646.

PurposeKnowledge about the germline mutational spectrum among Brazilian with hereditary breast and ovarian cancer (HBOC) is limited. Only five studies have performed comprehensive BRCA sequencing, corresponding to 1041 individuals among a Brazilian population of over 207 million people. Herein we aimed to determine the clinical and molecular characteristics of Brazilian patients who underwent oncogenetic counseling and genetic testing of a panel of high-risk and moderate-risk genes from 2009 to 2017.MethodsMassively parallel sequencing was applied in 157 individuals (132 breast cancer-affected and 25 breast cancer-unaffected individuals) selected according NCCN criteria for hereditary breast cancer. Analysis of mutation segregation in family members was performed by capillary bidirectional sequencing, clinical response after treament and survival analysis was estimated by Kaplan-Meier.ResultsNineteen germline variants were identified,15 pathogenic and 4 VUS (Variants of Uncertain Significance) in 27 individuals (27/157; 17% P < 0.0001) distributed among 7 genes. Sixty-eight percent of patients (13/19) harbor mutation in BRCA genes and 32% (6/19) in moderate risk genes. This is the first study reporting ATR deleterious germline mutation in association with hereditary breast cancer. Cancer-affected patients with moderate- risk mutation present a more aggressive phenotype, with bilateral cancer (25% vs. 13%, P = 0.0305), high-grade tumors (79.2% vs. 46.3%, P = 0.0001) and triple-negative (50% vs. 22.4%, P < 0.0001). However, no difference in the 5 years overall survival was observed between BRCA and moderate risk groups.ConclusionsThis work highlights the benefits of large-scale sequencing for oncogenetic counseling and extends our understanding about the genetics of hereditary breast cancer in the multi-ethnic Brazilian population.

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