Seborova Karolina, Hlavac Viktor, Holy Petr, Bjørklund Sunniva S, Fleischer Thomas, Rob Lukas, Hruda Martin, Bouda Jiri, Mrhalova Marcela, Allah Mohammad Moufaq Khatar Al Obeed, Vodicka Pavel, Fiala Ondrej, Soucek Pavel, Kristensen Vessela N, Vodickova Ludmila, Vaclavikova Radka
Toxicogenomics Unit, National Institute of Public Health in Prague, Prague, Czechia.
Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.
Front Oncol. 2022 Dec 2;12:1016958. doi: 10.3389/fonc.2022.1016958. eCollection 2022.
Epithelial ovarian carcinoma (EOC) is known for high mortality due to diagnosis at advanced stages and frequent therapy resistance. Previous findings suggested that the DNA repair system is involved in the therapeutic response of cancer patients and DNA repair genes are promising targets for novel therapies. This study aimed to address complex inter-relations among gene expression levels, methylation profiles, and somatic mutations in DNA repair genes and EOC prognosis and therapy resistance status. We found significant associations of expression with the presence of peritoneal metastases in EOC patients. The high-grade serous EOC subtype was enriched with mutations compared to other subtypes. Furthermore, somatic mutations in and were significantly associated with worse overall survival of EOC patients, and higher expression in platinum-resistant than platinum-sensitive patients was observed. We found higher methylation of in platinum-resistant than in platinum-sensitive patients. Somatic mutations in and were significantly associated with higher methylation in platinum-sensitive compared to platinum-resistant EOC patients. In conclusion, we discovered associations of several candidate genes from the DNA repair pathway with the prognosis and platinum resistance status of EOC patients, which deserve further validation as potential predictive biomarkers.
上皮性卵巢癌（EOC）因在晚期阶段才被诊断出来以及频繁出现治疗耐药性而具有高死亡率。先前的研究结果表明，DNA修复系统参与癌症患者的治疗反应，并且DNA修复基因是新型疗法的有前景的靶点。本研究旨在探讨DNA修复基因的基因表达水平、甲基化谱和体细胞突变之间的复杂相互关系以及EOC的预后和治疗耐药状态。我们发现EOC患者中基因表达与腹膜转移的存在之间存在显著关联。与其他亚型相比，高级别浆液性EOC亚型富含突变。此外，基因和基因的体细胞突变与EOC患者较差的总生存期显著相关，并且观察到铂耐药患者中的表达高于铂敏感患者。我们发现铂耐药患者中基因的甲基化高于铂敏感患者。与铂耐药的EOC患者相比，基因和基因的体细胞突变与铂敏感患者中更高的基因甲基化显著相关。总之，我们发现了DNA修复途径中的几个候选基因与EOC患者的预后和铂耐药状态之间的关联，这些关联作为潜在的预测生物标志物值得进一步验证。
