Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, PA 15261, USA.
Theranostics. 2020 Mar 4;10(9):3939-3951. doi: 10.7150/thno.39341. eCollection 2020.
: Loss of DNA damage repair (DDR) in the tumor is an established hallmark of sensitivity to DNA damaging agents such as chemotherapy. However, there has been scant investigation into gain-of-function alterations of DDR genes in cancer. This study aims to investigate to what extent copy number amplification of DDR genes occurs in cancer, and what are their impacts on tumor genome instability, patient prognosis and therapy outcome. : Retrospective analysis was performed on the clinical, genomics, and pharmacogenomics data from 10,489 tumors, matched peripheral blood samples, and 1,005 cancer cell lines. The key discoveries were verified by an independent patient cohort and experimental validations. : This study revealed that 13 of the 80 core DDR genes were significantly amplified and overexpressed across the pan-cancer scale. Tumors harboring DDR gene amplification exhibited decreased global mutation load and mechanism-specific mutation signature scores, suggesting an increased DDR proficiency in the DDR amplified tumors. Clinically, patients with DDR gene amplification showed poor prognosis in multiple cancer types. The most frequent Nibrin () gene amplification in ovarian cancer tumors was observed in 15 out of 31 independent ovarian cancer patients. overexpression in breast and ovarian cancer cells leads to BRCA1-dependent olaparib resistance by promoting the phosphorylation of ATM-S1981 and homology-dependent recombination efficiency. Finally, integration of the cancer pharmacogenomics database of 37 genome-instability targeting drugs across 505 cancer cell lines revealed significant correlations between DDR gene copy number amplification and DDR drug resistance, suggesting candidate targets for increasing patient treatment response. : DDR gene amplification can lead to chemotherapy resistance and poor overall survival by augmenting DDR. These amplified DDR genes may serve as actionable clinical biomarkers for cancer management.
肿瘤中 DNA 损伤修复 (DDR) 的缺失是对化疗等 DNA 损伤药物敏感的既定标志。然而，对癌症中 DDR 基因获得性功能改变的研究甚少。本研究旨在调查 DDR 基因的拷贝数扩增在癌症中发生的程度，以及它们对肿瘤基因组不稳定性、患者预后和治疗结果的影响。
对来自 10489 个肿瘤、匹配的外周血样本和 1005 个癌细胞系的临床、基因组学和药物基因组学数据进行了回顾性分析。通过独立的患者队列和实验验证验证了关键发现。
本研究揭示，在泛癌范围内，80 个核心 DDR 基因中有 13 个显著扩增和过表达。携带 DDR 基因扩增的肿瘤表现出全局突变负荷和机制特异性突变特征评分降低，表明 DDR 扩增肿瘤中 DDR 效率增加。临床上，DDR 基因扩增的患者在多种癌症类型中预后不良。在 31 名独立卵巢癌患者中观察到卵巢癌肿瘤中最常见的 Nibrin () 基因扩增 15 例。在乳腺癌和卵巢癌细胞中过表达会通过促进 ATM-S1981 的磷酸化和同源依赖性重组效率来导致奥拉帕利耐药。最后，整合 37 种针对基因组不稳定性的药物在 505 个癌细胞系中的癌症药物基因组学数据库显示 DDR 基因拷贝数扩增与 DDR 药物耐药性之间存在显著相关性，提示候选靶点可提高患者治疗反应。
DDR 基因扩增可通过增强 DDR 导致化疗耐药和总体生存率降低。这些扩增的 DDR 基因可作为癌症管理的可行临床生物标志物。
