Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary XXXX .

@entity1 @entity5 @entity470 @entity984 @entity2 @entity74 @entity420 @entity2220 @entity1722
INTRODUCTION: MET (Met proto-oncogene) activation either by gene amplification or mutation is implicated in various types of @entity1 @entity5 . For @entity2 , @entity74 is reported to occur in a subset of @entity420 . Although somatic mutations of @entity2220 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: MET gene copy number was determined by real-time quantitative polymerase chain reaction in 187 of the @entity1 with @entity2 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 @entity470 , @entity984 , and @entity1722 genes. RESULTS: All the instances of MET activation occurred in @entity1 with @entity420 . The prevalences of @entity74 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 @entity470 , @entity984 , and @entity1722 genes had strict mutual exclusionary relationships. CONCLUSIONS: About 5% of @entity420 in this cohort of Japanese @entity1 were driven by activated MET by gene amplification or splice mutations. Such @entity1 would be candidates for targeted therapy against MET.
