Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, Av. Senador Salgado Filho, s/n, Natal, 59078-970, Brazil.
Departamento de Pesquisa Translacional, Hospital Liga contra o Câncer, CECAN, Av. Miguel Castro, 1355, Natal, 59062-000, Brazil.
Breast Cancer Res Treat. 2018 Dec;172(3):637-646. doi: 10.1007/s10549-018-4938-0. Epub 2018 Aug 29.
Knowledge 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.
Massively 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.
Nineteen 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.
This 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.
巴西遗传性乳腺癌和卵巢癌（HBOC）患者的种系突变谱知识有限。仅有五项研究对巴西超过 2.07 亿人口中的 1041 个人进行了全面的 BRCA 测序。在此，我们旨在确定 2009 年至 2017 年间接受高危和中危基因组合遗传检测的巴西患者的临床和分子特征。
根据 NCCN 遗传性乳腺癌标准，对 157 名个体（132 名乳腺癌患者和 25 名乳腺癌未受影响的个体）进行了大规模平行测序。通过毛细管双向测序分析家系中突变的分离，通过 Kaplan-Meier 估计治疗后的临床反应和生存分析。
在 27 名个体（27/157；17% P < 0.0001）中鉴定出 19 种种系变异，其中 15 种为致病性变异，4 种为意义不明的变异（VUS），分布在 7 个基因中。68%的患者（13/19）携带 BRCA 基因突变，32%（6/19）携带中危基因突变。这是首次报道 ATR 有害种系突变与遗传性乳腺癌相关的研究。携带中危基因突变的癌症患者具有更具侵袭性的表型，双侧癌症（25% vs. 13%，P = 0.0305）、高级别肿瘤（79.2% vs. 46.3%，P = 0.0001）和三阴性（50% vs. 22.4%，P < 0.0001）。然而，BRCA 和中危组之间 5 年总生存率无差异。
这项工作强调了大规模测序在肿瘤遗传咨询中的益处，并扩展了我们对巴西多民族人群遗传性乳腺癌遗传的理解。
