High‐grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC‐related genes by high‐coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum‐based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co‐analyze the expression and mutational profiles of other key cancer genes.

中文翻译：

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高级别浆液性卵巢癌的靶向 DNA 测序与基因表达相结合，揭示了 TP53 突变与铂类耐药的关联

高级别浆液性卵巢癌（HGSC）是卵巢癌最常见的亚型，也是全世界最致命的妇科恶性肿瘤之一，原因是晚期诊断较晚且治疗频繁出现耐药性。在 47 名 HGSC 患者中，我们通过高覆盖率靶向 DNA 测序评估了 144 个已知或疑似 HGSC 相关基因的定制组的体细胞和种系遗传变异性，以确定与铂类治疗耐药性相关的遗传决定因素。在种系中，突变最多的基因是DNAH14(17%),RAD51B(17%),CFTR(13%),乳腺癌1(11%)，以及RAD51(11%)。从体细胞角度来看，突变最多的基因是TP53(98%)，其次是CSMD1/2/3(19/19/36%)，以及CFTR(23%)。将结果与一组类似的 35 名 HGSC 患者的全外显子组测序结果进行比较。体细胞变异TP53还使用 1287 个 HGSC 样本的 GENIE 数据进行了验证。我们的方法显示高影响体细胞和种系突变的患病率增加，特别是那些影响剪接位点的突变TP53，与验证数据集相比。另外，废话TP53体细胞突变与患者生存呈负相关。高架TP53转录水平与铂耐药性和存在相关TP53错义突变，同时减少TP53在携带预计具有高影响力的突变的肿瘤中发现了这一水平，这一点在癌症基因组图谱数据中得到了证实（n= 260）。靶向 DNA 测序TP53与转录本定量相结合可能有助于 HGSC 精准肿瘤学的概念。未来的研究应探索基于特定突变类型的 p53 通路，并共同分析其他关键癌症基因的表达和突变谱。