具有种系 BRCA1 和 BRCA2 致病性变异（BRCA 携带者）的个体患高级别浆液性卵巢癌 (HGSC) 的风险很高。 HGSC 主要由 TP53 突变驱动，但该基因的突变也常见于非癌组织中，作为正常人类衰老的一个特征。我们假设BRCA携带者的HGSC易感性可能与TP53体细胞进化的增加有关，这可以通过妇科液体活检中TP53突变的超深度测序来检测。双重测序用于在腹膜冲洗液和宫颈中高灵敏度地鉴定TP53突变在手术中从 60 名个体（包括 BRCA1 和 BRCA2 携带者以及非携带者）中收集了液基细胞学 (LBC)。对不同组间以及与 TP53 癌症突变的 TP53 突变致病性进行了比较。TP53 突变在宫颈 LBC 中比在腹膜洗液中更丰富，但在两种样本类型中都随着年龄的增长而增加。在腹膜冲洗中，但在宫颈 LBC 中，与非携带者相比，BRCA1 携带者的致病性 TP53 突变负荷增加，与年龄无关。五个人在腹膜冲洗液和宫颈 LBC 中具有相同的致病性 TP53 突变，但在血液中则不然。对手术时收集的腹膜冲洗液中的 TP53 突变进行超深度测序，显示 BRCA1 携带者中致病性 TP53 突变的负担增加。这种过量的致病性 TP53 突变可能与这些个体中 HGSC 风险升高有关。在一些患者中，在腹膜冲洗液和宫颈 LBC 中发现了一致的 TP53 突变，但细胞来源仍然未知，值得进一步研究。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Individuals with germline BRCA1 and BRCA2 pathogenic variants (BRCA carriers) are at high risk of developing high grade serous ovarian carcinoma (HGSC). HGSC is predominantly driven by TP53 mutations, but mutations in this gene are also commonly found in non-cancerous tissue as a feature of normal human aging. We hypothesized that HGSC predisposition in BRCA carriers may be related to increased TP53 somatic evolution, which could be detectable by ultra-deep sequencing of TP53 mutations in gynecological liquid biopsies.Duplex sequencing was used to identify TP53 mutations with high sensitivity in peritoneal washes and cervical liquid-based cytology (LBC) collected at surgery from 60 individuals including BRCA1 and BRCA2 carriers, and non-carriers. TP53 mutation pathogenicity was compared across groups and with TP53 cancer mutations.TP53 mutations were more abundant in cervical LBC than in peritoneal washes but increased with age in both sample types. In peritoneal washes, but not in cervical LBC, pathogenic TP53 mutation burden was increased in BRCA1 carriers compared to non-carriers, independently of age. Five individuals shared identical pathogenic TP53 mutations in peritoneal washes and cervical LBC, but not in blood.Ultra-deep sequencing of TP53 mutations in peritoneal washes collected at surgery reveals increased burden of pathogenic TP53 mutations in BRCA1 carriers. This excess of pathogenic TP53 mutations might be linked to the elevated risk of HGSC in these individuals. In some patients, concordant TP53 mutations were found in peritoneal washes and cervical LBCs, but the cell of origin remains unknown and deserves further investigation.Copyright © 2024 Elsevier Inc. All rights reserved.