Activation of MET by Gene Amplification or by Splice Mutations Deleting the Juxtamembrane Domain in Primary Resected Lung Cancers

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.