Oliveira Leandro Jonata de Carvalho, Rodrigues Amanda Muniz, Fernandes Carolina de Bustamante, Ramos do Rego Fernanda Orpinelli, Koyama Fernanda Christtanini, Souto Andreza Karine de Barros Almeida, Santana Thaiana Aragão, Gonzaga de Faria João Paulo, Lima Bulcão Marcela, Nascimento Ivana Lucia de Oliveira, Silva Ana Carolina Branco Neves, Gonçalves Isabela Pessoa Elias, Maia Rayana Elias, de Azevedo Renata Gondim Meira Velame, Galindo Layla Testa, Pachito Daniela Vianna, Cury Adriana, Zalis Mariano Gustavo, Ferrari Bruno Lemos, Garicochea Bernardo, Dienstmann Rodrigo
Oncoclinicas&CO - Medica Scientia Innovation Research (MedSir), São Paulo, Brazil.
Oncoclinicas (OC) Medicina de Precisão (OCPM), São Paulo, Brazil.
Front Oncol. 2024 Dec 17;14:1495605. doi: 10.3389/fonc.2024.1495605. eCollection 2024.
The prevalence of germline pathogenic/likely pathogenic variants (P/LP) in high and moderate penetrance (HMP) genes is approximately 7%-10% among breast cancer (BC) patients. The prevalence and spectrum of BC P/LP variants are affected by several factors. There are limited genetic data from Brazilian patients with BC.
This is a retrospective cross-sectional study that aims to evaluate the germline profile of P/LP variants in 13 HMP BC genes (, and ) in patients diagnosed with BC in Brazil. All patients were tested using multigene NGS panels covering from 35 to 105 genes. Primary endpoint was the prevalence of P/LP variants in BRCA1/2 and in other HMP genes. Secondary endpoints were stratified analyses according to age and BC subtype.
This cohort involved 2,208 patients with BC from 2019 to 2023. Most patients (79.7%) were from Southeastern Brazil. The median age at genetic testing was 47 years, and most patients (59.4%) were ≤50 years. The BC subtype was available in 641 cases: 264 patients (41.2%) were HR+/HER2-, 116 (18.1%) were HER2+, and 261 (40.7%) had triple-negative breast cancer (TNBC). Overall, 215 (9.7%) had a P/LP in HMP genes, including 5.8% in . The most frequent variants were found in , , and . The founder variant R337H accounted for 79% of all pathogenic variants, representing 1% of the overall population. Deleterious variants in were more common in patients ≤50 years (7.7%) and TNBC (10.7%). In other HMP BC genes, the prevalence of P/LP variants did not significantly vary according to age and BC molecular subtype. The overall VUS rate in HMP genes was 19.6%.
In Brazil, the epidemiology of deleterious variants in HMP is comparable to published US and EU cohorts. The Brazilian R337H is a prevalent variant in BC patients. Deleterious variants vary according to age and BC subtype. Our study gives a broader understanding of BC risk genes and has opened doors to optimized testing and surveillance strategies in Brazil.
在乳腺癌（BC）患者中，高、中度外显率（HMP）基因的种系致病性/可能致病性变异（P/LP）的发生率约为7%-10%。BC的P/LP变异的发生率和谱受到多种因素的影响。来自巴西BC患者的遗传数据有限。
这是一项回顾性横断面研究，旨在评估巴西诊断为BC的患者中13个HMP BC基因（、和）的P/LP变异的种系特征。所有患者均使用覆盖35至105个基因的多基因NGS面板进行检测。主要终点是BRCA1/2和其他HMP基因中P/LP变异的发生率。次要终点是根据年龄和BC亚型进行分层分析。
该队列纳入了2019年至2023年的2208例BC患者。大多数患者（79.7%）来自巴西东南部。基因检测时的中位年龄为47岁，大多数患者（59.4%）年龄≤50岁。641例患者有BC亚型信息：264例患者（41.2%）为HR+/HER2-，116例（18.1%）为HER2+，261例（40.7%）为三阴性乳腺癌（TNBC）。总体而言，215例（9.7%）患者在HMP基因中有P/LP变异，其中在中的发生率为5.8%。最常见的变异见于、和。奠基者变异R337H占所有致病性变异的79%，占总体人群的1%。中的有害变异在年龄≤50岁的患者（7.7%）和TNBC患者（10.7%）中更为常见。在其他HMP BC基因中，P/LP变异的发生率根据年龄和BC分子亚型没有显著差异。HMP基因中的总体意义未明变异（VUS）率为19.6%。
在巴西，HMP中有害变异的流行病学与已发表的美国和欧盟队列相当。巴西的R337H是BC患者中一种常见的变异。中的有害变异根据年龄和BC亚型而有所不同。我们的研究对BC风险基因有了更广泛的了解，并为巴西优化检测和监测策略打开了大门。
