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Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas

Abstract

Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours1–4. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8)5–6 Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7,16 and 17, and in men, by loss of the Y chromosome7. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation8–11. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D757537. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.

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References

  1. Zbar, B. et al. Hereditary papillary renal carcinoma. J. Urol. 151, 561–566, (1994).

    Article  CAS  Google Scholar 

  2. Zbar, B. et al. Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J. Urol. 153, 907–912 (1995).

    Article  CAS  Google Scholar 

  3. Bernades, P. et al. Cancer du rein gauche chez trois membres d'une meme fratrie. Sem.Hop. Paris 48, 2813–2818 (1972).

    Google Scholar 

  4. Bernues, M. et al. Cytogenetic characterization of a familial papillary renal cell carcinoma. Cancer Genet, and Cytogenet. 84, 123–127 (1995).

    Article  CAS  Google Scholar 

  5. Melman, K.L. & Rosen, S.W. Lindau's disease: review of the literature and study of a large kindred. Am. J. Med. 36, 595–617 (1964).

    Article  Google Scholar 

  6. Cohen, A.J. et al. Hereditary renal-cell carcinoma associated with a chromosomal translocation. NewEngl. J. Med. 301, 592–595 (1979).

    Article  CAS  Google Scholar 

  7. Kovacs, G. Molecular cytogenetics of renal tumours. Adv. Cancer Res. 62, 89–124 (1993).

    Article  CAS  Google Scholar 

  8. Latif, F. et al. Identification of the von Hippel-Lindau disease tumour suppressor gene. Science 260, 1317–1320 (1993).

    Article  CAS  Google Scholar 

  9. Schmidt, L. et al. Mechanism of tumourigenesis of renal carcinomas associated with the constitutional chromosome 3;8 translocation. Cancer J. from Sci. Am. 1, 191–196 (1995).

    CAS  Google Scholar 

  10. Gnarra, J.R. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature Genet. 7, 85–90 (1994).

    Article  CAS  Google Scholar 

  11. Herman, J.G. et al. Silencing of the VHL tumour suppressor gene by DNA methylation in renal carcinoma. Proc. Nat. Acad. Sci. USA 91, 9700–9704 (1994).

    Article  CAS  Google Scholar 

  12. Bergerheim, U.S.R. et al. Chromosomal gains and losses in sporadic and hereditary papillary renal carcinomas by comparative genomic hybridization. J. Urol. 155, 543A(1996).

    Google Scholar 

  13. Cooper, C.S. et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311, 29–33 (1984).

    Article  CAS  Google Scholar 

  14. Park, M. et al. Mechanism of met oncogene activation. Cell 45, 895–904 (1986).

    Article  CAS  Google Scholar 

  15. Wainwright, B.J. et al. Isolation of a human gene with protein sequence similarity to human and murine int-1 and the Drosophila segment polarity mutant wingless. EMBO J. 7, 1743–1748 (1988).

    Article  CAS  Google Scholar 

  16. Nusse, R., SVarmus, H.R. Wnt genes. Cell 69, 1073–1087 (1992).

    Article  CAS  Google Scholar 

  17. Stuart, E.T. & Gruss, P. PAX: Developmental control genes in cell growth and differentiation. Cell Growth Differ. 7, 405–412 (1996).

    CAS  PubMed  Google Scholar 

  18. LM.et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363, 458–460 (1993).

  19. Donis-Keller, H. et al. Mutations in the RET proto-oncogene associated with MEN 2A and FMTC. Hum. Mol. Genet 2, 851–856 (1993).

    Article  CAS  Google Scholar 

  20. Hofstra, R.M. et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367, 375–376 (1994).

    Article  CAS  Google Scholar 

  21. Piao, S. & Bernstein, A. A point mutation in the catalytic domain of c-kit induces growth factor independence, tumourigenicity and differentiation of mast cells. Blood 87, 3117–3123 (1996).

    CAS  PubMed  Google Scholar 

  22. Nagata, H. et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc. Natl. Acad. Sci. USA 92, 10560–10564 (1995).

    Article  CAS  Google Scholar 

  23. Bolino, A. et al. RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10, 2415–2419 (1995).

    CAS  PubMed  Google Scholar 

  24. Eng, C. et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medulllary thyroid carcinoma and in a family with FMTC. Oncogene 10, 509–513 (1995).

    CAS  PubMed  Google Scholar 

  25. Santoro, M. et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267, 381–383 (1995).

    Article  CAS  Google Scholar 

  26. Park, M. et al. Sequence of MET protooncogene cONA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc. Natl. Acad. Sci. USA 84, 6379–6383 (1987).

    Article  CAS  Google Scholar 

  27. Weidner, K.M., Sachs, M. & Birchmeier, W., Met receptor tyrosine kinase transduces motility, proliferation and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J. Cell Biol. 121, 145–154, (1993).

    Article  CAS  Google Scholar 

  28. Bladt, F., Riethmacher, D., Isenmann, S., Sguzzi, A. & Birchmeier, C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376, 768–771 (1995).

    Article  CAS  Google Scholar 

  29. Ponzetto, C. et al. c-met is amplified but not mutated in a cell line with an activated met tyrosine kinase. Oncogene 6, 553–559 (1991).

    CAS  PubMed  Google Scholar 

  30. Dl Renzo, M. et al. Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene 7, 2549–2553 (1992).

    Google Scholar 

  31. Bremner, R. & Balmain, A. Genetic changes in skin tumour progression: correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7. Cell 61, 407–417 (1990).

    Article  CAS  Google Scholar 

  32. Wirchubsky, Z., Wiener, F., Spira, J., Sumegi, J. & Klein, G. Triplication of one chromosome no 15 with an altered c-myc homologue in a T-cell lymphoma line of AKR origin (TIKAUT). Int. J. Cancer 33, 477–481 (1984).

    Article  Google Scholar 

  33. Bianchi, A.B., Alkaz, C.M. & Conti, C.J. Nonrandom duplication of the chromosome bearing a mutated Ha-ras-1 allele in mouse skin tumours. Proc. Natl. Acad. Sci. USA 87, 6902–6906 (1990).

    Article  CAS  Google Scholar 

  34. Meloni, A.M., Dobbs, R.M., Pontes, J.E. & Sandberg, A.A. Translocation [X;1] in papillary renal adenocarcinomaA new Cytogenetic subtype. Cancer Genet. Cytogenet. 65, 1–6 (1993).

    Article  CAS  Google Scholar 

  35. Sidhar, S.K. et al. The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Hum Mol. Genet. 5, 1333–1338 (1996).

    Article  CAS  Google Scholar 

  36. Weterman, M.A.J., Wilbrink, M. & van Kessel, A.G. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinoma. Proc. Natl. Acad. Sci. USA 93, 15294–15298 (1996).

    Article  CAS  Google Scholar 

  37. Choyke, P.L. et al. Imaging features of hereditary papillary renal carcinoma. J. Computer Assist. Tomography (in the press).

  38. Cottingham, R.W. Jr., Idury, R.M. & Schaffer, A.A. Faster sequential genetic linkage computations. Amer. J. Human Genet. 53, 252–263 (1993).

    Google Scholar 

  39. O'Connell, J.R.D.E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recording and fuzzy inheritance. Nature Genet. 11, 402–408 (1995).

    Article  CAS  Google Scholar 

  40. Weier, H.-U.G., Kleine, H.-O. & Gray, J.W. Labeling of the centromeric region on human chromosome 8 by in situ hybridization. Hum. Genet. 87, 489–494 (1991).

    Article  CAS  Google Scholar 

  41. Takahashi, M., Buma, Y. & Hiai, H. Isolation of ret proto-oncogene cDNA with an amino-terminal signal sequence. Oncogene 4, 805–806 (1989).

    CAS  Google Scholar 

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Schmidt, L., Duh, FM., Chen, F. et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16, 68–73 (1997). https://doi.org/10.1038/ng0597-68

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