Mohammad Al Obeed Allah, Esraa Ali, Ivona Krus, Petr Holý, Vojtěch Haničinec, Filip Ambrozkiewicz, Lukáš Rob, Martin Hruda, Marcela Mrhalová, Kateřina Kopečková, Alena Bartáková, Jiří Bouda, Alžběta Spálenková, Pavel Souček, Radka Václavíková
Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic.
Cancer Biol Ther. 2025 Dec;26(1):2543105. doi: 10.1080/15384047.2025.2543105. Epub 2025 Aug 10.
Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to follow up the findings of a previous whole-exome sequencing study using an orthogonal Sanger sequencing on the same patients and a separate set of 127 EOC patients ( = 177, all fresh frozen tumor samples). We focused on TP53 as a frequently mutated gene relevant for chemosensitivity, included KRAS as an additional therapeutically relevant target, complemented the study with transcript levels of both genes, and compared results with clinical parameters. All variants in TP53 and KRAS detected by exome sequencing were confirmed. KRAS mutated patients had significantly more frequent FIGO stages I or II ( = .002) and other than high-grade serous tumor subtypes (nonHGSCs) ( < .001), which was connected with lower KRAS transcript levels ( = .004). Patients with nonHGSC subtypes had less frequent TP53 mutations ( = .002). Carriers of TP53 variants disrupting the DNA binding loop had significantly longer platinum-free intervals than the rest ( = .037). Tumors bearing nonsense, frameshift, or splice site TP53 variants had a significantly lower TP53 transcript level, while those with missense variants had significantly higher levels than wild types ( < .001). The normalized intratumoral TP53 and KRAS transcript levels were correlated, and patients with co-mutated genes had poorer overall survival than others ( = .015). Protein levels of both genes significantly correlated with their respective transcripts ( = .028 and = .001, respectively). Our study points to as a target for future therapy of nonHGSCs and reveals the prognostic value of variants in the DNA binding loop.
鉴于上皮性卵巢癌（EOC）化疗耐药患者的预后不佳，我们旨在通过对同一批患者进行正交桑格测序以及对另外127例EOC患者（共177例，所有样本均为新鲜冷冻肿瘤样本）进行研究，以跟进先前全外显子测序研究的结果。我们将TP53作为与化疗敏感性相关的常见突变基因进行重点研究，将KRAS作为另一个与治疗相关的靶点纳入研究，补充这两个基因的转录水平研究，并将结果与临床参数进行比较。通过外显子测序检测到的TP53和KRAS的所有变异均得到证实。KRAS突变患者的国际妇产科联盟（FIGO）分期为I期或II期的频率显著更高（P = 0.002），且非高级别浆液性肿瘤亚型（nonHGSCs）的频率更高（P < 0.001），这与较低的KRAS转录水平相关（P = 0.004）。非HGSC亚型患者的TP53突变频率较低（P = 0.002）。破坏DNA结合环的TP53变异携带者的无铂间期明显长于其他患者（P = 0.037）。携带无义、移码或剪接位点TP53变异的肿瘤的TP53转录水平显著较低，而携带错义变异的肿瘤的TP53转录水平显著高于野生型肿瘤（P < 0.001）。肿瘤内TP53和KRAS的标准化转录水平相关联，基因共突变的患者的总生存期比其他患者更差（P = 0.015）。这两个基因的蛋白质水平与其各自的转录本显著相关（分别为P = 0.028和P = 0.001）。我们的研究指出[此处原文缺失具体内容]作为未来非HGSCs治疗的靶点，并揭示了DNA结合环中[此处原文缺失具体内容]变异的预后价值。
