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.