DNA Damage Response and Repair Pathway Alteration and Its Association With Tumor Mutation Burden and Platinum-Based Chemotherapy in SCLC
DNA Damage Response and Repair Pathway Alteration and Its Association With Tumor Mutation Burden and Platinum-Based Chemotherapy in SCLC
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DOI：
10.1016/j.jtho.2019.05.014
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发表时间：
2019-09-01
影响因子：
20.4
通讯作者：
Park, Keunchil
中科院分区：
文献类型：
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作者：
Park, Sehhoon;Lee, Hayoon;Park, Keunchil
引言：DNA损伤反应和修复（DDR）途径受损是铂敏感性的预测性生物标志物。方法：对100例广泛期（艾德）和66例局限期（LD）小细胞肺癌（SCLC）患者的381个靶基因进行测序分析。检测到的突变被分类为双链断裂（DSB）（n = 82）：同源重组（n = 54）、非同源末端连接（n = 19）和范可尼贫血（n = 32）;或单链断裂（SSB）（n = 31）：错配修复（n = 19）、碱基切除修复（n = 7）和核苷酸切除修复（n = 6）。与完整DDR通路患者（n = 70）相比，在同源重组（p < 0.001）、非同源末端连接（p = 0.002）、错配修复（p < 0.001）、DSB（p <0.001）和SSB（p < 0.001）患者中观察到更高的TMB。基于TMB水平的生存分析显示在艾德患者中没有预测或预后价值。在LD患者中，在TMB高于中位数的患者中观察到同步放化疗的无进展生存期（风险比[HR] = 0.497，p = 0.015）和总生存期（HR = 0.383，p = 0.010）延长。个体DDR通路改变在接受铂类化疗的艾德患者中没有显示生存益处。在LD患者中，凡可尼贫血基因组突变的患者的无进展生存期较短（HR = 2.048，p = 0.036），以初始treatment.Conclusions：DDR通路的改变，DSB和SSB，在SCLC中与高TMB呈正相关。然而，它在预测铂疗效方面显示出有限的价值。(C)2019年国际肺癌研究协会。爱思唯尔公司出版All rights reserved.
Introduction: Impairment in DNA damage response and repair (DDR) pathway is known as a predictive biomarker of platinum sensitivity. Recently, DDR alteration is reemphasized as a predictive biomarker of immune checkpoint inhibitor due to its positive correlation to tumor mutation burden (TMB).Methods: Target gene sequencing (381 genes) was conducted from 100 extensive disease (ED) and 66 limited disease (LD) patients with SCLC. Detected mutations were classified as double-strand breaks (DSB) (n = 82): homologous recombination (n = 54), non-homologous end joining (n = 19), and Fanconi anemia (n = 32); or single-strand breaks (SSB) (n = 31): mismatch repair (n = 19), base excision repair (n = 7), and nucleotide excision repair (n = 6).Results: Compared to patients with an intact DDR pathway (n = 70), a higher TMB was observed in patients with homologous recombination (p < 0.001), non-homologous end joining (p = 0.002), mismatch repair (p < 0.001), DSB (p < 0.001), and SSB (p < 0.001). Survival analyses based on TMB level showed no predictive or prognostic values in ED patients. In LD patients, prolonged progression-free survival (hazard ratio [HR] = 0.497, p = 0.015), and overall survival (HR = 0.383, p = 0.010) to concurrent chemoradiotherapy were observed in those with TMB above median. Individual DDR pathway alteration showed no survival benefit in ED patients receiving platinum-based chemotherapy. In LD patients, those with mutations in the Fanconi anemia gene set had shorter progression-free survival (HR = 2.048, p = 0.036) to initial treatment.Conclusions: DDR pathway alterations, both DSB and SSB, in SCLC have a positive correlation with high TMB. However, it has shown limited value in prediction of platinum efficacy. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.