title: Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers.
abstract: BACKGROUND
  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.
  
  
  METHODS
  MET 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.
authors.affiliation: Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Onozato
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kosaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D001483:Base Sequence; D018196:Carcinoma, Adenosquamous / Q000235:genetics / Q000556:secondary / Q000601:surgery; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000556:secondary / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000556:secondary / Q000601:surgery; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011013:Pneumonectomy; D011379:Prognosis; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: D066246:ErbB Receptors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D017978:Receptors, Growth Factor; D044767:Ubiquitin-Protein Ligases; D018631:ras Proteins; C117307:KRAS protein, human; C000715470:MAS1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human