Tumoral Genetics and Virology Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Bioinformatics and Computational Biology Laboratory, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Cancer Med. 2024 Feb;13(3):e6729. doi: 10.1002/cam4.6729. Epub 2024 Feb 2.
Approximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high-grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss-of-function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression-free survival and overall survival.
The study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2.
A total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression-free survival.
Frequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non-functional or non-functional somatic variants, while eight 14.2% presented likely non-functional or non-functional somatic variants in BRCA1 or BRCA2.
约有 3/4 的卵巢癌在晚期被诊断出来，其中高级别上皮性卵巢癌（EOC）占 90%。EOC 具有较高的基因组不稳定性和与同源重组突变修复途径（HR）相关的基因的体细胞失活变异，如 BRCA1 和 BRCA2 以及 TP53。在 EOC 中鉴定 HR 基因的种系变异与治疗铂类耐药肿瘤和基于合成致死性的复发性肿瘤有关，如 PARP 抑制剂。HR 基因体细胞变异的患者也可能从这些治疗中受益。在这项工作中，分析了巴西 EOC 患者队列中 BRCA1、BRCA2 和 TP53 的体细胞变异频率，估计了肿瘤组织中变异的比例及其与无进展生存期和总生存期的关系。
该研究对 56 名患者的配对血液/肿瘤样本进行了研究。通过大规模平行测序获得了 BRCA1、BRCA2 和 TP53 的种系和肿瘤序列。使用 HaplotypeCaller 方法对种系变异进行了调用，并用 Mutect2 对体细胞变异进行了调用。
共发现 26 种种系变异，7 名患者在 BRCA1 或 BRCA2 中存在种系致病性或可能致病性变异。肿瘤组织分析发现，41 名患者中有 52 种体细胞变异，其中 43 种体细胞变异影响或可能影响蛋白功能。生存分析显示，肿瘤分期与总生存期（OS）相关，而 TP53 存在体细胞突变与 OS 或无进展生存期无关。
BRCA1 和 BRCA2 中致病性或可能致病性种系变异的频率（12.5%）低于其他研究。TP53 是肿瘤中最常发生改变的基因，62.5%的肿瘤存在可能无功能或无功能的体细胞变异，而 8 个（14.2%）肿瘤存在可能无功能或无功能的 BRCA1 或 BRCA2 体细胞变异。
