Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer
Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer
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DNA 损伤修复途径的拷贝数扩增增强了癌症的治疗耐药性
DOI：
10.7150/thno.39341
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发表时间：
2020-03
期刊：
影响因子：
12.4
通讯作者：
Da Yang
中科院分区：
文献类型：
--
作者：
Zhiyuan Wu;Sihan Li;Xuemei Tang;Yue Wang;Weiwei Guo;Guojun Cao;Kun Chen;Min Zhang;Ming Guan;Da Yang
理论基础：肿瘤中DNA损伤修复(DDR)的丢失是对DNA损伤药物(如化疗)敏感的公认标志。然而，关于DDR基因在癌症中的功能获得改变的研究很少。本研究旨在探讨DDR基因拷贝数扩增在肿瘤中发生的程度，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。方法：对10,489个肿瘤、匹配的外周血样和1,005个癌细胞系的临床、基因组学和药物基因组学数据进行回顾性分析。这些关键发现通过独立的患者队列和实验验证得到了验证。结果：这项研究揭示了80个核心DDR基因中的13个在泛癌范围内显著扩增和过度表达。携带DDR基因扩增的肿瘤表现出整体突变负荷和机制特异性突变签名分数的降低，这表明DDR扩增的肿瘤的DDR熟练程度提高。临床上，DDR基因扩增的患者在多种癌症类型中预后不良。卵巢癌中Nibrin(NBN)基因扩增频率最高的有15例。NBN在乳腺和卵巢癌细胞中的过表达通过促进ATM-S1981的磷酸化和同源依赖的重组效率而导致BRCA1依赖的奥拉帕利耐药。最后，整合了跨越505个癌细胞系的37种基因组不稳定性靶向药物的癌症药物基因组学数据库，发现DDR基因拷贝数扩增与DDR耐药性之间存在显著相关性，为提高患者治疗反应提出了候选靶点。主要结论：DDR基因扩增可通过增加DDR而导致化疗耐药和总生存率下降。这些扩增的DDR基因可作为癌症治疗的临床生物标记物。
Rationale: 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. Methods: 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. Results: 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 (NBN) gene amplification in ovarian cancer tumors was observed in 15 out of 31 independent ovarian cancer patients. NBN 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. Principal Conclusions: 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.
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