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Novel Somatic Mutations of the MET Oncogene in Human Carcinoma Metastases Activating Cell Motility and Invasion¹

Laboratory of Cancer Genetics [A. L., M. O., S. P., M. F. D. R.] and Division of Molecular Oncology [P. M. C.], Institute for Cancer Research and Treatment, and Thoracic Surgery Unit, Department of Clinical Physiopathology [E. R., A. O.], University of Torino Medical School, Torino, Italy 10060

Several gene mutations responsible for human cancer initiation have been discovered, whereas only a few have been identified in association with the progression to metastasis. In this study, we screened a large panel of human sporadic cancers, metastases, and tumor cell lines for mutations in the tyrosine kinase domain of the MET receptor, crucially involved in invasive cell growth and motility during embryogenesis. MET activating mutations have been described previously in hereditary papillary renal cell carcinoma and in a few sporadic tumors. Summarizing results of this and our previous studies, we did not detect mutations in the MET kinase domain from 153 sporadic human cancers and 25 cancer cell lines, whereas we found somatic MET mutations in 10 of 46 lymph nodal and 2 of 14 pulmonary metastases. We identified four MET mutations in metastases. Two were known as MET germ-line mutations (H1112R and Y1248C), which predispose to hereditary renal cell carcinoma. One of the two novel mutations (N1118Y) changed an asparagine in the region of the glycine-rich ATP binding site, which is highly conserved in all of the kinases. The other (Y1253D) changed a critical tyrosine, known to regulate MET kinase activity, to a negatively charged residue.

The MET receptors carrying either the N1118Y or the Y1253D mutation were constitutively active and conferred a motile-invasive phenotype on transduced carcinoma cells. The latter phenotype was additionally stimulated by the MET receptor ligand scatter factor/hepatocyte growth factor. These data suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis.

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