Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas
Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas
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DOI：
10.1200/jco.2016.71.9096
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发表时间：
2017-09-01
影响因子：
45.3
通讯作者：
Ju, Young Seok
中科院分区：
文献类型：
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作者：
Lee, June-Koo;Lee, Junehawk;Ju, Young Seok
目的EGFR突变型肺腺癌（LADC）向小细胞肺癌（SCLC）的组织学转化是表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）耐药的主要机制之一。然而，分子发病机制仍不清楚。MethodsWe调查了21例晚期EGFR突变LADC转化为EGFR TKI耐药SCLC患者。其中，全基因组测序应用于从4名患者在不同时间点获得的9个肿瘤，以重建其克隆进化历史，并检测小细胞转化的遗传预测因子。免疫组化在210肺癌tissues.ResultsWe确定，EGFR TKI耐药LADC和SCLC共享一个共同的克隆起源，并经历分支的进化轨迹验证的结果。SCLC祖先与LADC细胞的克隆分化发生在第一次EGFR TKI治疗之前，并且在测序肿瘤的早期LADC阶段观察到RB 1和TP 53的完全失活。我们在75例接受EGFR TKI治疗的患者的早期LADC组织中扩展了免疫组化结果; Rb和p53的失活在小细胞转化组中比在非转化组中显著更频繁（82%v 3%;比值比，131; 95%CI，19.9至859）。在预定队列登记的患者中（n = 65），携带完全失活Rb和p53的EGFR突变LADC发生小细胞转化的风险增加433（相对风险为42.8; 95%CI为5.88 - 311）。分支特异性突变签名分析显示，载脂蛋白B mRNA编辑酶，催化多肽样（APOBEC）诱导的超突变是频繁的分支向小细胞transformation.ConclusionEGFR TKI耐药SCLC分支早期从LADC克隆港完全灭活RB 1和TP 53。EGFR TKI处理的LADC中RB 1和TP 53状态的评价可为预测小细胞转化提供信息。(C)2017年美国临床肿瘤学会
PurposeHistologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear.MethodsWe investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI-resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues.ResultsWe identified that EGFR TKI-resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell-transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 433greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-induced hypermutation was frequent in the branches toward small-cell transformation.ConclusionEGFR TKI-resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI-treated LADCs is informative in predicting small-cell transformation. (C) 2017 by American Society of Clinical Oncology