Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas

A metastatic cancer develops by accumulation of mutations in genes that con trol growth, survival and spreading. The latter genes have not yet been ide ntified. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosin e kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identified two somatic mutations: the Y1230C, known as a MET germline m utation which predisposes to hereditary renal cell carcinoma, and the Y1235 D that is novel and changes a critical tyrosine, known to regulate MET kina se activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET un dergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary canc ers to metastasis.