College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China.
State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Gynecol Oncol. 2020 Jul;158(1):66-76. doi: 10.1016/j.ygyno.2020.04.695. Epub 2020 May 8.
Platinum-based chemotherapy remains the first-line treatment for ovarian carcinoma by inducing DNA damage. The therapeutic impact of clonal and subclonal somatic mutations in DNA damage repair (DDR) pathways remains unexplored.
We performed an integrated analysis to infer the clonality of somatic deleterious mutations in 385 ovarian carcinomas treated with platinum-based chemotherapy. The Kaplan-Meier method was performed for visualization and the differences between survival curves were calculated by log-rank test. Proportional hazards models were used to estimate relative hazards for platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS).
We found that somatic deleterious mutations in DDR pathways exhibited widespread clonal heterogeneity, and that patients with DDR clonal mutations exhibited a "hypermutator phenotype". Clonal somatic mutations in homologous recombination repair (HRR) pathway were significantly associated with better OS (HR = 0.19 (95% CI, 0.06-0.59), P = 0.0044) and PFS (HR = 0.20 (95% CI, 0.08-0.49), P = 0.0005) than HRR wild-type, while HRR subclonal mutations were not associated with prognosis. Moreover, HRR clonal mutations were associated with significantly higher chemotherapy sensitive rate (P = 0.0027) and longer PFI (HR = 0.20 (95% CI, 0.08-0.49), P = 0.0005) than HRR wild-type, while HRR subclonal mutations were not. We validated our findings using an independent cohort of 93 ovarian cancer patients that received platinum-based chemotherapy.
HRR clonal mutations, but not subclonal mutations, were associated with improved survival, chemotherapy response, and genome instability compared with HRR wild-type.
铂类化疗通过诱导 DNA 损伤仍然是卵巢癌的一线治疗方法。DNA 损伤修复 (DDR) 途径中的克隆和亚克隆体细胞突变的治疗影响仍未得到探索。
我们对 385 例接受铂类化疗治疗的卵巢癌患者进行了 DDR 中体细胞有害突变的克隆性综合分析。采用 Kaplan-Meier 法进行可视化，对数秩检验计算生存曲线之间的差异。比例风险模型用于估计无铂间隔（PFI）、无进展生存期（PFS）和总生存期（OS）的相对风险。
我们发现 DDR 途径中的体细胞有害突变表现出广泛的克隆异质性，并且 DDR 克隆突变的患者表现出“超突变表型”。同源重组修复（HRR）途径中的克隆体细胞突变与更好的 OS（HR=0.19（95%CI，0.06-0.59），P=0.0044）和 PFS（HR=0.20（95%CI，0.08-0.49），P=0.0005）显著相关，而 HRR 野生型则没有，而 HRR 亚克隆突变与预后无关。此外，HRR 克隆突变与化疗敏感率显著升高（P=0.0027）和 PFI 延长相关（HR=0.20（95%CI，0.08-0.49），P=0.0005），而 HRR 野生型则没有，而 HRR 亚克隆突变则没有。我们使用接受铂类化疗的 93 例卵巢癌患者的独立队列验证了我们的发现。
与 HRR 野生型相比，HRR 克隆突变而非亚克隆突变与改善生存、化疗反应和基因组不稳定性相关。
