DNAH10 mutation correlates with cisplatin sensitivity and tumor mutation burden in small-cell lung cancer
DNAH10 mutation correlates with cisplatin sensitivity and tumor mutation burden in small-cell lung cancer
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DNAH10 突变与小细胞肺癌的顺铂敏感性和肿瘤突变负荷相关
DOI：
10.18632/aging.102683
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发表时间：
2020-01-31
期刊：
影响因子：
5.2
通讯作者：
Guo, Linlang
中科院分区：
文献类型：
--
作者：
Li, Man;Lin, Anqi;Guo, Linlang
在过去的几年里，基于铂的化疗一直是小细胞肺癌（SCLC）患者的标准一线治疗。然而，患者的进展主要是由于化疗耐药性的快速发展。此外，SCLC发生顺铂耐药的机制仍不确定。在这里，我们分析了来自癌症药物敏感性基因组学（GDSC， N=55）的全外显子组测序（WES）数据集，以及来自已发表队列（N=101）的WES数据和总生存率（OS），以寻找顺铂耐药靶基因和与不良预后相关的基因。我们使用队列（NCT03162705）作为验证集。我们应用单样本基因集富集分析（ssGSEA）探讨顺铂耐药的潜在分子机制。SCLC中DNAH10突变与顺铂耐药（P=0.0350）、较差的OS（HR:3.445；P=0.00035）和较差的无进展生存（PFS）（P=0.0142）显著相关。ssGSEA显示，在dnah10突变的细胞系中，FGFR的负调控、FGF的SPRY调控以及非典型WNT和PI3K/AKT/IKK信号通路的正调控存在差异上调或下调。在dnah10突变的细胞系中观察到更高的TMB。综上所述，DNAH10突变可能在预测SCLC顺铂耐药和生存不良方面具有潜在价值。此外，DNAH10突变可能与SCLC的高TMB呈正相关。
Chemotherapies based on platinum have been the standard first-line treatment for patients with small-cell lung cancer(SCLC) in the past years. However, the progression of patients occurs mostly due to rapid development of resistance to chemotherapy. In addition, the mechanisms involved in development of cisplatin-resistance in SCLC remain undetermined. Here, we analyzed whole-exome sequencing(WES) datasets from Genomics of Drug Sensitivity in Cancer(GDSC, N=55) and WES data and overall survival(OS) from a published cohort(N=101) to search for cisplatin-resistant target genes and genes associated with poor prognosis. We use our cohort(NCT03162705) as the validation set. We applied single sample gene set enrichment analysis(ssGSEA) to explore the potential molecular mechanisms of cisplatin-resistance. DNAH10 mutations in SCLC was significantly associated with cisplatin-resistance(P=0.0350), poor OS(HR:3.445;P=0.00035) and worse progression-free survival (PFS)(P=0.0142). ssGSEA showed that the negative regulation of FGFR, the SPRY regulation of FGF, and the positive regulation of noncanonical WNT and PI3K/AKT/IKK signaling pathways are differentially up- or downregulated in DNAH10-mutated cell lines. A higher TMB was observed in DNAH10-mutated cell lines. Taken together, DNAH10 mutations may have a potential value in prediction of cisplatin resistance and poor survival in SCLC. Moreover, DNAH10 mutations may have a positive correlation with high TMB in SCLC.