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

Oncogene volume 19, pages 1547–1555 (2000)Cite this article

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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References

  • Bardelli A, Longati P, Gramaglia D, Basilico C, Tamagnone L, Giordano S, Ballinari D, Michieli P and Comoglio PM . 1998 Proc Natl Acad Sci USA 95: 14379–14383

  • Bardelli A, Pugliese L and Comoglio PM . 1997 Biochim Biophys Acta 1333: M41–M51

  • Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ and Plowman GD . 1998 EMBO J 17: 3052–3065

  • Bladt F, Riethmacher D, Isenmann S, Aguzzi A and Birchmeier C . 1995 Nature 376: 768–771

  • Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF and Aaronson SA . 1991 Science 251: 802–804

  • Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, Corio R, Lee D, Greenberg B, Koch W and Sidransky D . 1996 Cancer Res 56: 2488–2492

  • Di Renzo MF, Narsimhan RP, Olivero M, Bretti S, Giordano S, Medico E, Gaglia P, Zara P and Comoglio PM . 1991 Oncogene 6: 1997–2003

  • Di Renzo MF, Olivero M, Ferro S, Prat M, Bongarzone I, Pilotti S, Belfiore A, Costantino A, Vigneri R, Pierotti MA and et al. 1992 Oncogene 7: 2549–2553

  • Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, Giordano S, Plebani M, Gespach C and Comoglio PM . 1995a Clin Cancer Res 1: 147–154

  • Di Renzo MF, Poulsom R, Olivero M, Comoglio PM and Lemoine NR . 1995b Cancer Res 55: 1129–1138

  • Fidler IJ and Ellis LM . 1994 Cell 79: 185–188

  • Fischer J, Palmedo G, von Knobloch R, Bugert P, Prayer-Galetti T, Pagano F and Kovacs G . 1998 Oncogene 17: 733–739

  • Galeazzi E, Olivero M, Gervasio FC, De Stefani A, Valente G, Comoglio PM, Di Renzo MF and Cortesina G . 1997 Eur Arch Otorhinolaryngol Suppl 1: S138–S143

  • Ghoussoub RA, Dillon DA, D'Aquila T, Rimm EB, Fearon ER and Rimm DL . 1998 Cancer 82: 1513–1520

  • Giordano S, Bardelli A, Zhen Z, Menard S, Ponzetto C and Comoglio PM . 1997 Proc Natl Acad Sci USA 94: 13868–13872

  • Giordano S, Maffe A, Williams TA, Artigiani S, Gual P, Bardelli A, Basilico C, Michieli P and Comoglio PM . 2000 FASEB J, 14: 399–406

  • Giordano S, Ponzetto C, Di Renzo MF, Cooper CS and Comoglio PM . 1989 Nature 339: 155–156

  • Hasegawa Y, Takeda S, Ichii S, Koizumi K, Maruyama M, Fujii A, Ohta H, Nakajima T, Okuda M, Baba S and et al. 1995 Oncogene 10: 1441–1445

  • Iyer A, Kmiecik TE, Park M, Daar I, Blair D, Dunn KJ, Sutrave P, Ihle JN, Bodescot M and Vande Woude GF . 1990 Cell Growth Differ 1: 87–95

  • Jeffers M, Fiscella M, Webb CP, Anver M, Koochekpour S and Vande Woude GF . 1998 Proc Natl Acad Sci USA 95: 14417–14422

  • Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B and Vande Woude GF . 1997 Proc Natl Acad Sci USA 94: 11445–11450

  • Liang TJ, Reid AE, Xavier R, Cardiff RD and Wang TC . 1996 J Clin Invest 97: 2872–2877

  • Longati P, Bardelli A, Ponzetto C, Naldini L and Comoglio PM . 1994 Oncogene 9: 49–57

  • Maina F, Casagranda F, Audero E, Simeone A, Comoglio PM, Klein R and Ponzetto C . 1996 Cell 87: 531–542

  • Marais R, Light Y, Paterson HF, Mason CS and Marshall CJ . 1997 J Biol Chem 272: 4378–4383

  • Marshall DD and Kornberg LJ . 1998 Laryngoscope 108: 1413–1417

  • Masumoto A and Yamamoto N . 1991 Biochem Biophys Res Commun 174: 90–95

  • Medico E, Mongiovi' AM, Huff J, Jelinek M-A, Follenzi A, Gaudino G, Parsons JT and Comoglio PM . 1996 Mol Biol Cell 7: 495–504

  • Meiners S, Brinkmann V, Naundorf H and Birchmeier W . 1998 Oncogene 16: 9–20

  • Michieli P, Basilico C, Pennacchietti S, Maffe' A, Tamagnone L, Giordano S, Bardelli A and Comoglio PM . 1999 Oncogene 18: 5221–5231

  • Naldini L, Vigna E, Narsimhan RP, Gaudino G, Zarnegar R, Michalopoulos GK and Comoglio PM . 1991 Oncogene 6: 501–504

  • Olivero M, Valente G, Bardelli A, Longati P, Ferrero N, Cracco C, Terrone C, Rocca-Rossetti S, Comoglio PM and Di Renzo MF . 1999 Int J Cancer 82: 640–643

  • Otsuka T, Takayama H, Sharp R, Celli G, LaRochelle WJ, Bottaro DP, Ellmore N, Vieira W, Owens JW, Anver M and Merlino G . 1998 Cancer Res 58: 5157–5167

  • Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, Lee SH, Yoo NJ, Jang JJ, Pack S, Zhuang Z, Schmidt L, Zbar B and Lee JY . 1999 Cancer Res 59: 307–310

  • Ponzetto C, Zhen Z, Audero E, Maina F, Bardelli A, Basile ML, Giordano S, Narsimhan R and Comoglio P . 1996 J Biol Chem 271: 14119–14123

  • Rong S, Segal S, Anver M, Resau JH and Vande Woude GF . 1994 Proc Natl Acad Sci USA 91: 4731–4735

  • Sable CL, Filippa N, Hemmings B and Van Obberghen E . 1997 FEBS Lett 409: 253–257

  • Sawatsubashi M, Sasatomi E, Mizokami H, Tokunaga O and Shin T . 1998 Virchows Arch 432: 331–335

  • Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T and Zbar B . 1997 Nat Genet 16: 68–73

  • Schmidt L, Junker K, Nakaigawa N, Kinjerski T, Weirich G, Miller M, Lubensky I, Neumann HP, Brauch H, Decker J, Vocke C, Brown JA, Jenkins R, Richard S, Bergerheim U, Gerrard B, Dean M, Linehan WM and Zbar B . 1999 Oncogene 18: 2343–2350

  • Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, Walther M, Linehan WM and Zbar B . 1998 Cancer Res 58: 1719–1722

  • Sonnenberg E, Weidner KM and Birchmeier C . 1993 Exs 65: 381–394

  • Tsubouchi H, Niitani Y, Hirono S, Nakayama H, Gohda E, Arakaki N, Sakiyama O, Takahashi K, Kimoto M, Kawakami S and et al. 1991 Hepatology 13: 1–5

  • Yamashita J, Ogawa M, Yamashita S, Nomura K, Kuramoto M, Saishoji T and Shin S . 1994 Cancer Res 54: 1630–1633

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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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Authors and Affiliations

  1. Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment (IRCC), SP 142, Km. 3.95, 10060 Candiolo (Torino), Italy

    M F Di Renzo, M Olivero, T Martone & P Maggiora

  2. Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), SP 142, Km. 3.95, 10060 Candiolo (Torino), Italy

    A Maffe, S Giordano & P M Comoglio

  3. Department of Biomedical Sciences, Otolaryngology Unit, University of Torino Medical School, 10126, Torino, Italy

    M F Di Renzo, M Olivero, A Maffe, P Maggiora, S Giordano & P M Comoglio

  4. Department of Clinical Physiopathology, Otolaryngology Unit, University of Torino Medical School, 10126 Torino, Italy

    T Martone, A De Stefani & G Cortesina

  5. Department of Medical Sciences, Amedeo Avogadro University, Novara, 28100, Italy

    G Valente

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  1. M F Di Renzo
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  2. M Olivero
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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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