Activation of MET by Gene Amplification or by Splice Mutations Deleting the Juxtamembrane Domain in Primary Resected Lung Cancers
Activation of MET by Gene Amplification or by Splice Mutations Deleting the Juxtamembrane Domain in Primary Resected Lung Cancers
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DOI：
10.1097/jto.0b013e3181913e0e
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发表时间：
2009-01-01
影响因子：
20.4
通讯作者：
Mitsudomi, Tetsuya
中科院分区：
文献类型：
--
作者：
Onozato, Ryoichi;Kosaka, Takayuki;Mitsudomi, Tetsuya
导读：MET （MET原癌基因）通过基因扩增或突变激活与多种类型的人类癌症有关，对于肺癌，据报道MET基因扩增发生在腺癌的一个亚群中。尽管肺腺癌中MET的体细胞突变很少见，但迄今为止报道的除一例外，所有突变都涉及剪切突变，删除了用于结合c-Cbl e3连接酶的近膜结构域；通常这种结合会导致泛素化和受体降解，而该结构域的丢失会导致MET激活。本研究的目的是阐明MET激活在肺癌发生中的作用。材料与方法：187例肺癌患者采用实时定量聚合酶链反应测定ME-T基因拷贝数，262例患者采用直接测序法检测MET基因剪接突变缺失近膜结构域。结果与多种临床和病理特征相关，包括表皮生长因子受体、KRAS和HER2基因的突变。结果：所有的MET激活都发生在腺癌患者中。MET基因扩增和剪接突变的发生率分别为1.4%（2 / 148）和3.3%（7 / 211）。我们确定了四种不同的内含子突变，破坏了基因组DNA的剪接一致序列。MET的激活与表皮生长因子受体、KRAS和HER2基因的突变具有严格的互斥关系。结论：在这组日本患者中，约5%的肺腺癌是由基因扩增或剪接突变激活的MET驱动的。这些患者可能是针对MET的靶向治疗的候选者。
Introduction: MET (Met proto-oncogene) activation either by gene amplification or mutation is implicated in Various types of human cancers, For lung cancer, MET gene amplification is reported to occur in a subset of adenocarcinomas. Although somatic mutations of MET in lung adenocarcinomas are rare, all but one of those reported so far entail a splice mutation deleting the juxtamembrane domain for binding the c-Cbl E3-ligase; normally such binding leads to ubiquitination and receptor degradation, and loss of this domain leads to MET activation. The purpose of this study was to clarify in the role of MET activation in lung carcinogenesis.Materials and Methods: ME-T gene copy number was determined by real-time quantitative polymerase chain reaction in 187 of the patients with lung cancer and the MET gene splice Mutation deleting the juxtamembrane domain was examined by direct sequencing in 262. The results were correlated with various clinical and pathologic features including mutations of the epidermal growth factor receptor, KRAS, and HER2 genes.Results: All the instances of MET activation occurred in patients with adenocarcinomas. The prevalences of MET gene amplification and splice mutations were 1.4% (2 of 148) and 3.3% (7 of 211), respectively. We identified four different intronic mutations that disrupted a splice consensus sequence in genomic DNA. Activation of MET and mutations of the epidermal growth factor receptor, KRAS, and HER2 genes had strict mutual exclusionary relationships.Conclusions: About 5% of pulmonary adenocarcinomas in this cohort of Japanese patients were driven by activated MET by gene amplification or splice mutations. Such patients would be candidates for targeted therapy against MET.