Abstract
A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identified. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine 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 mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase 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 undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis.
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Acknowledgements
We thank G Petruccelli and R Albano for technical support and S Patane for his enthusiastic help in performing experiments. We thank M Lobianco and E Wright for secretarial help and for reading the English. C Ponzetto and L Naldini are gratefully acknowledged for helpful discussion and critical reading of the manuscript. This work was supported by the Italian Association for Cancer Research, the CNR ‘Target Project on Biotechnology’, and the Giovanni Armenise-Harvard Foundation for Advanced Scientific Research.
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Di Renzo, M., Olivero, M., Martone, T. et al. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19, 1547–1555 (2000). https://doi.org/10.1038/sj.onc.1203455
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DOI: https://doi.org/10.1038/sj.onc.1203455
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