Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion

Annalisa Lorenzato, Martina Olivero, Salvatore Patané, Edoardo Rosso, Alberto Oliaro, Paolo M. Comoglio, Maria Flavia Di Renzo

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Abstract

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.

Original languageEnglish
Pages (from-to)7025-7030
Number of pages6
JournalCancer Research
Volume62
Issue number23
Publication statusPublished - Dec 1 2002

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Oncogenes
Cell Movement
Neoplasm Metastasis
Carcinoma
Mutation
Proto-Oncogene Proteins c-met
Neoplasms
Phosphotransferases
Renal Cell Carcinoma
Phenotype
Hepatocyte Growth Factor
Germ-Line Mutation
Asparagine
Lymph
Tumor Cell Line
Glycine
Embryonic Development
Tyrosine
Adenosine Triphosphate
Binding Sites

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. / Lorenzato, Annalisa; Olivero, Martina; Patané, Salvatore; Rosso, Edoardo; Oliaro, Alberto; Comoglio, Paolo M.; Di Renzo, Maria Flavia.

In: Cancer Research, Vol. 62, No. 23, 01.12.2002, p. 7025-7030.

Research output: Contribution to journalArticle

Lorenzato, Annalisa ; Olivero, Martina ; Patané, Salvatore ; Rosso, Edoardo ; Oliaro, Alberto ; Comoglio, Paolo M. ; Di Renzo, Maria Flavia. / Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. In: Cancer Research. 2002 ; Vol. 62, No. 23. pp. 7025-7030.
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