Nuffield Department of Medicine, University of Oxford, Old Road Campus, OX3 7FZ, United Kingdom.
Nuffield Department of Medicine, University of Oxford, Old Road Campus, OX3 7FZ, United Kingdom.
DNA Repair (Amst). 2019 Jun;78:142-153. doi: 10.1016/j.dnarep.2019.04.008. Epub 2019 Apr 24.
Overactive DNA repair contributes to therapeutic resistance in cancer. However, pan-cancer comparative studies investigating the contribution of all DNA repair genes in cancer progression employing an integrated approach have remained limited. We performed a multi-cohort retrospective analysis to determine the prognostic significance of 138 DNA repair genes in 16 cancer types (n = 16,225). Cox proportional hazards analyses revealed a significant variation in the number of prognostic genes between cancers; 81 genes were prognostic in clear cell renal cell carcinoma while only two genes were prognostic in glioblastoma. We reasoned that genes that were commonly prognostic in highly correlated cancers revealed by Spearman's correlation analysis could be harnessed as a molecular signature for risk assessment. A 10-gene signature, uniting prognostic genes that were common in highly correlated cancers, was significantly associated with overall survival in patients with clear cell renal cell (P < 0.0001), papillary renal cell (P = 0.0007), liver (P = 0.002), lung (P = 0.028), pancreas (P = 0.00013) or endometrial (P = 0.00063) cancers. Receiver operating characteristic analyses revealed that a combined model of the 10-gene signature and tumor staging outperformed either classifier when considered alone. Multivariate Cox regression models incorporating additional clinicopathological features showed that the signature was an independent predictor of overall survival. Tumor hypoxia is associated with adverse outcomes. Consistent across all six cancers, patients with high 10-gene and high hypoxia scores had significantly higher mortality rates compared to those with low 10-gene and low hypoxia scores. Functional enrichment analyses revealed that high mortality rates in patients with high 10-gene scores were attributable to an overproliferation phenotype. Death risk in these patients was further exacerbated by concurrent mutations of a cell cycle checkpoint protein, TP53. The 10-gene signature identified tumors with heightened DNA repair ability. This information has the potential to radically change prognosis through the use of adjuvant DNA repair inhibitors with chemotherapeutic drugs.
过度活跃的 DNA 修复会导致癌症的治疗耐药性。然而，采用综合方法研究所有 DNA 修复基因在癌症进展中的作用的泛癌症比较研究仍然有限。我们进行了多队列回顾性分析，以确定 16 种癌症类型中 138 个 DNA 修复基因的预后意义（n=16225）。Cox 比例风险分析显示，癌症之间预后基因的数量存在显著差异；81 个基因在透明细胞肾细胞癌中具有预后意义，而胶质母细胞瘤中只有两个基因具有预后意义。我们推断，通过 Spearman 相关分析显示在高度相关的癌症中具有共同预后意义的基因可以被用作风险评估的分子特征。一个由在高度相关的癌症中常见的预后基因组成的 10 基因特征与透明细胞肾细胞癌（P<0.0001）、乳头状肾细胞癌（P=0.0007）、肝（P=0.002）、肺（P=0.028）、胰腺（P=0.00013）或子宫内膜（P=0.00063）癌症患者的总生存期显著相关。受试者工作特征分析表明，与单独考虑时相比，10 基因特征和肿瘤分期的组合模型表现更好。纳入其他临床病理特征的多变量 Cox 回归模型显示，该特征是总生存期的独立预测因子。肿瘤缺氧与不良预后相关。在所有六种癌症中一致，高 10 基因和高缺氧评分的患者的死亡率明显高于低 10 基因和低缺氧评分的患者。功能富集分析显示，高 10 基因评分患者的高死亡率归因于过度增殖表型。这些患者的死亡风险因细胞周期检查点蛋白 TP53 的同时突变而进一步加剧。10 基因特征识别出具有增强 DNA 修复能力的肿瘤。这些信息有可能通过使用化疗药物联合辅助 DNA 修复抑制剂来彻底改变预后。
