Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Novel mutations of the MET proto-oncogene in papillary renal carcinomas

Abstract

Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET proto-oncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected five novel missense mutations; three of five mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grubendorf F, Raue F, Ritter MM and Hoppner W. . 1998 J. Clin. Endo. Metab. 83: 770–774.

  • Borden EC, Hogan TF and Voelkel JG. . 1982 Cancer Res. 42: 4948–4953.

  • Brown JA, Anderl KL, Borell TJ, Qian J, Bostwick DJ and Jenkins RB. . 1997 J. Urology 158: 370–374.

  • Di Renzo MF, Olivero M, Serini G, Orlandi F, Pilotti S, Belfiore A, Costantino A, Vigneri R, Angeli A, Pierotti MA and Comoglio PM. . 1995 J. Endocrinol. Invest. 18: 134–139.

  • Duh F-M, Scherer SW, Tsui L-C, Lerman M, Zbar B and Schmidt L. . 1997 Oncogene 15: 1583–1586.

  • Ermis A, Henn W, Remberger K, Hopf C, Hopf T and Zang KD. . 1995 Human Genet. 96: 651–654.

  • Fattoruso O, Quadro L, Libroia A, Verga U, Lupoli G, Cascone E and Colantuoni V. . 1998 Human Mutation Supplement 1: S167–S171.

  • Fischer J, Palmedo G and Kovacs G. . 1998 Proc. Amer. Assoc. Can. Res. 39: 130.

  • Grignon DJ and Eble JN. . 1998 Semin. Diagnos. Pathol. 15: 41–53.

  • Hanafusa H. . 1986 In: Oncogenes and Growth Control. Kahn P and Graf T. (ed.).. Springer-Verlag: Berlin, Heidelberg. pp. 100–105.

    Book  Google Scholar 

  • Huang H, Qian C, Jenkins RB and Smith DI. . 1998 Genes, Chromosomes and Cancer 21: 152–159.

  • Hubbard SR, Wei L, Ellis L and Hendrikson WA. . 1994 Nature 372: 746–754.

  • Hubbard SR. . 1997 EMBO J. 16: 5572–5581.

  • 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.

  • Jeffers M, Rong S and Vande Woude GF. . 1996 J. Mol. Med. 74: 505–513.

  • Kovacs G. . 1993 Adv. Cancer Res. 62: 89–124.

  • Levy JB, Iba H and Hanafusa H. . 1986 Proc. Natl. Acad. Sci. USA 83: 4228–4232.

  • Lin JC, Scherer SW, Tougar L, Traverso G, Tsui L-C, Andrulis IL, Jothy S and Park M. . 1996 Oncogene 13: 2001–2008.

  • Park M, Dean M, Kaul K, Braun MJ, Gonda MA and Vande Woude GF. . 1987 Proc. Nat. Acad. Sci. USA 84: 6379–6383.

  • Pignon J-M. . 1997 Hematol. Cell Ther. 39: 114–116.

  • Santoro MM, Penengo L, Minetto M, Orecchia S, Cili M and Gaudino G. . 1998 Oncogene 17: 741–749.

  • Schmidt L, Li F, Brown RS, Berg S, Chen F, Wei M-W, Tory K, Lerman MI and Zbar B. . 1995 Cancer J. Sci. Amer. 1: 191–196.

  • Schmidt L, Duh F-M, Chen F, Kishida T, Glenn G, Choyke P, Scherer S, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJM, Walther MM, Tsui L-C, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM and Zbar B. . 1997 Nature Genet. 16: 68–73.

  • Schmidt L, Li H, Wei M-H, Lerman MI, Zbar B and Tory K. . 1993 Human Mol. Genet. 2: 817–818.

  • 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.

  • Shu H-K, Pelley RJ and Kung H-J. . 1990 Proc. Natl. Acad. Sci. USA 87: 9103–9107.

  • Shu H-K, Pelley RJ and Kung HJ. . 1991 Virology 65: 6173–6180.

  • Shu H-K, Chang C-M, Lakshmeswari R, Ling L, Castellano CH, Walterm E, Pelley RJ and Kung H-J. . 1994 Mol. Cell Biol. 14: 6868–6878.

  • Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwillian R, Ross M, Linehan WM, Birdsall S, Shipley J and Cooper CS. . 1996 Hum. Mol. Genet. 5: 1333–1338.

  • Weterman MA, Wilbrink M and van Kessel AG. . 1996 Proc. Natl. Acad. Sci. USA 93: 15294–15298.

  • Ullrich A and Schlessinger J. . 1990 Cell 61: 203–212.

  • Underhill PA, Jin L, Zemano R, Oefner PJ and Cavalli-Sforza LL. . 1996 Proc. Natl. Acad. Sci. USA 93: 196–200.

  • Zbar B, Tory K, Merino M, Schmidt L, Glenn G, Choyke P, Walther MM and Linehan WM. . 1994 J. Urol. 15: 561–566.

  • Zbar B and Lerman M. . 1998 Adv. Cancer Res. 75: 163–201.

  • Zenklusen JC, Thompson JC, Troncoso P, Kagan J and Conti CJ. . 1994 Cancer Res. 54: 6370–6373.

  • Zenklusen JC, Weitzel JN, Ball HG and Conti JC. . 1995 Oncogene 11: 359–363.

  • Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E, Pham T, Candidas S, Weil RJ, Lubensky I, Linehan WM, Zbar B and Weirich G. . 1998 Nature Gen. 20: 66–69.

Download references

Acknowledgements

We thank Drs Scott Kern, Bert Vogelstein, Marcel Mannens, Marius Skudlinski, Gloria Niehans, Holger Moch, Webster Cavanee, Sandra Bigner, Burt Feuerstein, McClellan Walther, Kimberly Newsom Johnson/Vanderbilt Tissue Procurement Lab, Sharon Howard/Fox Chase Cancer Center, Paolo Radice, Michael Hughson, Masahiro Yao, Suzanne Topalian, Virginia LiVolsi, and Bruce Weintraub for providing tumor samples or DNA for mutation analysis. In addition we thank Dr Gerd Riedasch, Department of Urology, Rupert-Karls-University, Heidelberg, Germany for clinical evaluation of PRC patients and Dr JA Brown, Mayo Clinic (Rochester, MN, USA) for karyotypic and histologic analyses of metanephric adenomas. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-56000 and under contract with ABL (MM). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The publisher or recipient acknowledges right of the US Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmidt, L., Junker, K., Nakaigawa, N. et al. Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18, 2343–2350 (1999). https://doi.org/10.1038/sj.onc.1202547

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202547

Keywords

This article is cited by

Search

Quick links