Genetic screening and molecular characterization of MET alterations in non-small cell lung cancer
Genetic screening and molecular characterization of MET alterations in non-small cell lung cancer
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DOI：
10.1007/s12094-017-1799-7
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发表时间：
2018-07-01
影响因子：
3.4
通讯作者：
Sanchez-Cespedes, M.
中科院分区：
文献类型：
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作者：
Saigi, M.;McLeer-Florin, A.;Sanchez-Cespedes, M.
由于外显子14跳跃（METex 14）突变或基因扩增导致的MET异常激活是非小细胞肺癌（NSCLC）的致癌机制，也是潜在的治疗靶点。本研究的目的是表征MET的变化在一个队列的NSCLC患者接受手术治疗。157 NSCLC的各种组织病理学，包括肺肉瘤样癌（PSC），MET的变化进行了测试。分别通过桑格测序、荧光原位杂交和免疫组化检测METex 14突变、MET拷贝数改变和MET蛋白水平。其他重要的癌基因和下游效应物phopho-S6的免疫染色也同时发生改变。在7个肿瘤中检测到METex 14突变和MET扩增。MET基因改变主要见于肺腺癌（ADC）和PSC组织病理学。在大多数MET扩增的肿瘤中发现了高水平的MET蛋白，但不是在所有METex 14突变的肿瘤中。在大约一半的MET激活的肿瘤中观察到强烈的磷酸-S6染色。一个具有METex 14的肿瘤表现出同时的ERBB 2扩增JET激活，无论是METex 14突变还是扩增，都是早期NSCLC亚组的特征，并且可以与ERBB 2扩增共存。这可能具有潜在的治疗意义。METex 14突变的存在与低水平的MET蛋白相关，这可能限制总MET免疫染色作为预先选择患者进行MET靶向治疗的标志物的使用。
Aberrant activation of MET as a result of exon 14-skipping (METex14) mutations or gene amplification is an oncogenic mechanism in non-small cell lung carcinoma (NSCLC) and a potential therapeutic target. The purpose of this study was to characterize MET alterations in a cohort of NSCLC patients treated with surgery.157 NSCLCs of various histopathologies, including pulmonary sarcomatoid carcinomas (PSC), were tested for MET alterations. METex14 mutations, MET copy number alterations and the levels of MET protein were determined by Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry, respectively. Concurrent alterations of other important cancer genes and immunostaining of the downstream effector, phopho-S6, were also determined.METex14 mutations and MET amplification were detected in seven tumors. MET genetic alterations were found predominantly in the lung adenocarcinoma (ADC) and PSC histopathologies. High levels of MET protein were found in most MET-amplified tumors, but not in all METex14-mutated tumors. Strong phopho-S6 staining was observed in about half of the MET-activated tumors. One tumor with METex14 exhibited concurrent ERBB2 amplification.MET activation, by either METex14 mutations or amplification, is characteristic of a subset of early stage NSCLCs and may coexist with ERBB2 amplification. This may have potential therapeutic implications. The presence of METex14 mutations was associated with low levels of MET protein, which may limit the use of total MET immunostaining as a marker for preselecting patients for MET-targeted therapies.