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Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers.
- Source :
-
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2009 Jan; Vol. 4 (1), pp. 5-11. - Publication Year :
- 2009
-
Abstract
- 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.<br />Materials and 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.<br />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.<br />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.
- Subjects :
- Adenocarcinoma genetics
Adenocarcinoma secondary
Adenocarcinoma surgery
Adult
Aged
Aged, 80 and over
Base Sequence
Carcinoma, Adenosquamous genetics
Carcinoma, Adenosquamous secondary
Carcinoma, Adenosquamous surgery
Carcinoma, Large Cell genetics
Carcinoma, Large Cell secondary
Carcinoma, Large Cell surgery
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell secondary
Carcinoma, Squamous Cell surgery
ErbB Receptors genetics
Female
Gene Dosage
Humans
Lung Neoplasms pathology
Lung Neoplasms surgery
Male
Middle Aged
Molecular Sequence Data
Neoplasm Staging
Pneumonectomy
Prognosis
Protein Structure, Tertiary
Proto-Oncogene Mas
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-cbl metabolism
Proto-Oncogene Proteins c-met
Proto-Oncogene Proteins p21(ras)
Receptor, ErbB-2 genetics
Receptors, Growth Factor metabolism
Sequence Deletion
Small Cell Lung Carcinoma secondary
Small Cell Lung Carcinoma surgery
Tumor Cells, Cultured
Ubiquitin-Protein Ligases metabolism
ras Proteins genetics
Alternative Splicing
Gene Amplification
Lung Neoplasms genetics
Mutation genetics
Proto-Oncogene Proteins genetics
Receptors, Growth Factor genetics
Small Cell Lung Carcinoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1556-1380
- Volume :
- 4
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 19096300
- Full Text :
- https://doi.org/10.1097/JTO.0b013e3181913e0e