Whole-exome sequencing identifies key mutated genes in T790M wildtype/cMET-unamplified lung adenocarcinoma with acquired resistance to first-generation EGFR tyrosine kinase inhibitors
Whole-exome sequencing identifies key mutated genes in T790M wildtype/cMET-unamplified lung adenocarcinoma with acquired resistance to first-generation EGFR tyrosine kinase inhibitors
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全外显子组测序鉴定出对第一代 EGFR 酪氨酸激酶抑制剂获得性耐药的 T790M 野生型/cMET 未扩增肺腺癌中的关键突变基因
DOI：
10.1007/s00432-018-2634-4
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发表时间：
2018-06-01
影响因子：
3.6
通讯作者：
Wang, Changli
中科院分区：
文献类型：
--
作者：
Li, Chenguang;Liu, Hailin;Wang, Changli
目的肺癌是全球癌症相关死亡的主要原因。携带EGFR激活突变的肺腺癌将不可避免地获得对第一代EGFR酪氨酸激酶抑制剂（TKI）的耐药性。EGFR T790 M突变和cMET扩增是常见机制。方法收集69例对第一代EGFR TKI（吉非替尼、厄洛替尼或埃克替尼）获得性耐药的IIIB-IV期NSCLC患者的肿瘤和血液样本，分析其基因组变异对耐药的影响。采用cobas（R）和Droplet digital PCR（ddPCR）检测肿瘤样品和血浆ctDNA中的T790 M突变。通过荧光原位杂交（FISH）评价cMET扩增。对4例T790 M野生型/cMET未扩增样本进行外显子组测序。在进行肿瘤再活检的21个样本中，14个为T790 M阳性（66.7%）。在7份T790 M阴性样本中的3份中鉴定出cMET扩增。通过对4例T790 M野生型/cMET未扩增标本和配对白色血细胞进行外显子组测序，发现BRAF、FGFR 1、PAK 1、PCNT、PEBP 4和SOX 3等候选关键突变基因。结论EGFR T790 M突变和cMET扩增是导致肺腺癌EGFR TKI耐药的主要机制。本研究中确定的这些关键突变基因需要在大量患者中进一步验证。
Purpose Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma harboring EGFR-activating mutations will inevitably acquire resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs). EGFR T790M mutation and cMET amplification are common mechanisms. Further study is needed to explore unknown genomic alterations contributing to drug resistance.Methods Tumor and blood samples from 69 stage IIIB-IV NSCLC patients defined as acquired resistance to first-generation EGFR TKIs (gefitinib, erlotinib or ecotinib) were collected. The cobas((R)) and Droplet digital PCR (ddPCR) were used to detect T790M mutations in tumor samples and plasma ctDNA. cMET amplification was evaluated by fluorescence in situ hybridization (FISH). Exome sequencing was performed in four T790M wildtype/cMET-unamplified samples.Results The overall T790M-positive rate was 52.2% considering all testing methods. Out of 21 samples in which tumor re-biopsy was performed, 14 were T790M positive (66.7%). cMET amplification was identified in three out of seven T790M-negative samples. Exome sequencing in four T790M wildtype/cMET-unamplified samples and paired white blood cells identified a cohort of candidate key mutated genes including BRAF, FGFR1, PAK1, PCNT, PEBP4 and SOX3.Conclusions EGFR T790M mutation and cMET amplification are main mechanisms leading to EGFR TKI resistance in lung adenocarcinoma. These key mutated genes identified in the present study would need further validation in large number of patients.