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. 1998 Jun;62(6):1475–1483. doi: 10.1086/301888

An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation.

D Bodmer 1, M J Eleveld 1, M J Ligtenberg 1, M A Weterman 1, B A Janssen 1, D F Smeets 1, P E de Wit 1, A van den Berg 1, E van den Berg 1, M I Koolen 1, A Geurts van Kessel 1
PMCID: PMC1377167  PMID: 9585616

Abstract

Through allele-segregation and loss-of-heterozygosity analyses, we demonstrated loss of the translocation-derivative chromosome 3 in five independent renal cell tumors of the clear-cell type, obtained from three members of a family in which a constitutional t(2;3)(q35;q21) was encountered. In addition, analysis of the von Hippel-Lindau gene, VHL, revealed distinct insertion, deletion, and substitution mutations in four of the five tumors tested. On the basis of these results, we conclude that, in this familial case, an alternative route for renal cell carcinoma development is implied. In contrast to the first hit in the generally accepted two-hit tumor-suppressor model proposed by Knudson, the familial translocation in this case may act as a primary oncogenic event leading to (nondisjunctional) loss of the der(3) chromosome harboring the VHL tumor-suppressor gene. The risk of developing renal cell cancer may be correlated directly with the extent of somatic (kidney) mosaicism resulting from this loss.

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Selected References

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  1. Beaudet A. L., Tsui L. C. A suggested nomenclature for designating mutations. Hum Mutat. 1993;2(4):245–248. doi: 10.1002/humu.1380020402. [DOI] [PubMed] [Google Scholar]
  2. Cohen A. J., Li F. P., Berg S., Marchetto D. J., Tsai S., Jacobs S. C., Brown R. S. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med. 1979 Sep 13;301(11):592–595. doi: 10.1056/NEJM197909133011107. [DOI] [PubMed] [Google Scholar]
  3. Decker H. J., Weidt E. J., Brieger J. The von Hippel-Lindau tumor suppressor gene. A rare and intriguing disease opening new insight into basic mechanisms of carcinogenesis. Cancer Genet Cytogenet. 1997 Jan;93(1):74–83. doi: 10.1016/s0165-4608(96)00296-8. [DOI] [PubMed] [Google Scholar]
  4. Foster K., Prowse A., van den Berg A., Fleming S., Hulsbeek M. M., Crossey P. A., Richards F. M., Cairns P., Affara N. A., Ferguson-Smith M. A. Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet. 1994 Dec;3(12):2169–2173. doi: 10.1093/hmg/3.12.2169. [DOI] [PubMed] [Google Scholar]
  5. Geurts van Kessel A. H., Tetteroo P. A., von dem Borne A. E., Hagemeijer A., Bootsma D. Expression of human myeloid-associated surface antigens in human-mouse myeloid cell hybrids. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3748–3752. doi: 10.1073/pnas.80.12.3748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gnarra J. R., Lerman M. I., Zbar B., Linehan W. M. Genetics of renal-cell carcinoma and evidence for a critical role for von Hippel-Lindau in renal tumorigenesis. Semin Oncol. 1995 Feb;22(1):3–8. [PubMed] [Google Scholar]
  7. Gnarra J. R., Tory K., Weng Y., Schmidt L., Wei M. H., Li H., Latif F., Liu S., Chen F., Duh F. M. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994 May;7(1):85–90. doi: 10.1038/ng0594-85. [DOI] [PubMed] [Google Scholar]
  8. Herman J. G., Latif F., Weng Y., Lerman M. I., Zbar B., Liu S., Samid D., Duan D. S., Gnarra J. R., Linehan W. M. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700–9704. doi: 10.1073/pnas.91.21.9700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Knudson A. G. Antioncogenes and human cancer. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10914–10921. doi: 10.1073/pnas.90.23.10914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kok K., Naylor S. L., Buys C. H. Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res. 1997;71:27–92. doi: 10.1016/s0065-230x(08)60096-2. [DOI] [PubMed] [Google Scholar]
  11. Koolen M. I., van der Meyden A. P., Bodmer D., Eleveld M., van der Looij E., Brunner H., Smits A., van den Berg E., Smeets D., Geurts van Kessel A. A familial case of renal cell carcinoma and a t(2;3) chromosome translocation. Kidney Int. 1998 Feb;53(2):273–275. doi: 10.1046/j.1523-1755.1998.00762.x. [DOI] [PubMed] [Google Scholar]
  12. Kovacs G., Brusa P., De Riese W. Tissue-specific expression of a constitutional 3;6 translocation: development of multiple bilateral renal-cell carcinomas. Int J Cancer. 1989 Mar 15;43(3):422–427. doi: 10.1002/ijc.2910430313. [DOI] [PubMed] [Google Scholar]
  13. Kovacs G., Frisch S. Clonal chromosome abnormalities in tumor cells from patients with sporadic renal cell carcinomas. Cancer Res. 1989 Feb 1;49(3):651–659. [PubMed] [Google Scholar]
  14. Kovacs G., Hoene E. Loss of der(3) in renal carcinoma cells of a patient with constitutional t(3;12). Hum Genet. 1988 Feb;78(2):148–150. doi: 10.1007/BF00278186. [DOI] [PubMed] [Google Scholar]
  15. Kovacs G., Kung H. F. Nonhomologous chromatid exchange in hereditary and sporadic renal cell carcinomas. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):194–198. doi: 10.1073/pnas.88.1.194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kovacs G. Molecular cytogenetics of renal cell tumors. Adv Cancer Res. 1993;62:89–124. doi: 10.1016/s0065-230x(08)60316-4. [DOI] [PubMed] [Google Scholar]
  17. Li F. P., Decker H. J., Zbar B., Stanton V. P., Jr, Kovacs G., Seizinger B. R., Aburatani H., Sandberg A. A., Berg S., Hosoe S. Clinical and genetic studies of renal cell carcinomas in a family with a constitutional chromosome 3;8 translocation. Genetics of familial renal carcinoma. Ann Intern Med. 1993 Jan 15;118(2):106–111. doi: 10.7326/0003-4819-118-2-199301150-00005. [DOI] [PubMed] [Google Scholar]
  18. Meloni A. M., Bridge J., Sandberg A. A. Reviews on chromosome studies in urological tumors. I. Renal tumors. J Urol. 1992 Aug;148(2 Pt 1):253–265. doi: 10.1016/s0022-5347(17)36565-5. [DOI] [PubMed] [Google Scholar]
  19. Motzer R. J., Bander N. H., Nanus D. M. Renal-cell carcinoma. N Engl J Med. 1996 Sep 19;335(12):865–875. doi: 10.1056/NEJM199609193351207. [DOI] [PubMed] [Google Scholar]
  20. Ohta M., Inoue H., Cotticelli M. G., Kastury K., Baffa R., Palazzo J., Siprashvili Z., Mori M., McCue P., Druck T. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell. 1996 Feb 23;84(4):587–597. doi: 10.1016/s0092-8674(00)81034-x. [DOI] [PubMed] [Google Scholar]
  21. Schmidt L., Duh F. M., Chen F., Kishida T., Glenn G., Choyke P., Scherer S. W., Zhuang Z., Lubensky I., Dean M. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997 May;16(1):68–73. doi: 10.1038/ng0597-68. [DOI] [PubMed] [Google Scholar]
  22. Schmidt L., Li F., Brown R. S., Berg S., Chen F., Wei M. H., Tory K., Lerman I., Zbar B. Mechanism of tumorigenesis of renal carcinomas associated with the constitutional chromosome 3;8 translocation. Cancer J Sci Am. 1995 Sep-Oct;1(3):191–195. [PubMed] [Google Scholar]
  23. Shuin T., Kondo K., Torigoe S., Kishida T., Kubota Y., Hosaka M., Nagashima Y., Kitamura H., Latif F., Zbar B. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res. 1994 Jun 1;54(11):2852–2855. [PubMed] [Google Scholar]
  24. Sidhar S. K., Clark J., Gill S., Hamoudi R., Crew A. J., Gwilliam R., Ross M., Linehan W. M., Birdsall S., Shipley J. 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. 1996 Sep;5(9):1333–1338. doi: 10.1093/hmg/5.9.1333. [DOI] [PubMed] [Google Scholar]
  25. Smith D. I., Glover T. W., Gemmill R., Drabkin H., O'Connell P., Naylor S. L. Report and abstracts of the fifth international workshop on human chromosome 3 mapping 1994. Ann Arbor, Michigan, May 8-9, 1994. Cytogenet Cell Genet. 1995;68(3-4):125–146. doi: 10.1159/000133907. [DOI] [PubMed] [Google Scholar]
  26. Spur N. K., Bashir R., Bushby K., Cox A., Cox S., Hilde Brandt F., Hill N., Kao F. T., Krols L., Marzella R. Report and abstracts of the Fourth International Workshop on Human Chromosome 2 Mapping 1996. Cytogenet Cell Genet. 1996;73(4):255–273. doi: 10.1159/000134352. [DOI] [PubMed] [Google Scholar]
  27. Stein W. D., Stein A. D. Familial and sporadic human renal cell carcinoma: evidence against a double-loss mechanism of carcinogenesis. J Clin Epidemiol. 1995 Jun;48(6):767–777. doi: 10.1016/0895-4356(94)00192-s. [DOI] [PubMed] [Google Scholar]
  28. Weterman M. A., Wilbrink M., Geurts van Kessel A. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15294–15298. doi: 10.1073/pnas.93.26.15294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Weterman M. A., Wilbrink M., Janssen I., Janssen H. A., van den Berg E., Fisher S. E., Craig I., Geurts van Kessel A. Molecular cloning of the papillary renal cell carcinoma-associated translocation (X;1)(p11;q21) breakpoint. Cytogenet Cell Genet. 1996;75(1):2–6. doi: 10.1159/000134444. [DOI] [PubMed] [Google Scholar]
  30. Zbar B., Kishida T., Chen F., Schmidt L., Maher E. R., Richards F. M., Crossey P. A., Webster A. R., Affara N. A., Ferguson-Smith M. A. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348–357. doi: 10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  31. Zhuang Z., Gnarra J. R., Dudley C. F., Zbar B., Linehan W. M., Lubensky I. A. Detection of von Hippel-Lindau disease gene mutations in paraffin-embedded sporadic renal cell carcinoma specimens. Mod Pathol. 1996 Aug;9(8):838–842. [PubMed] [Google Scholar]
  32. van den Berg A., Buys C. H. Involvement of multiple loci on chromosome 3 in renal cell cancer development. Genes Chromosomes Cancer. 1997 Jun;19(2):59–76. doi: 10.1002/(sici)1098-2264(199706)19:2<59::aid-gcc1>3.3.co;2-o. [DOI] [PubMed] [Google Scholar]
  33. van den Berg A., Draaijers T. G., Kok K., Timmer T., Van der Veen A. Y., Veldhuis P. M., de Leij L., Gerhartz C. D., Naylor S. L., Smith D. I. Normal FHIT transcripts in renal cell cancer- and lung cancer-derived cell lines, including a cell line with a homozygous deletion in the FRA3B region. Genes Chromosomes Cancer. 1997 Aug;19(4):220–227. doi: 10.1002/(sici)1098-2264(199708)19:4<220::aid-gcc3>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  34. van den Berg A., Hulsbeek M. F., de Jong D., Kok K., Veldhuis P. M., Roche J., Buys C. H. Major role for a 3p21 region and lack of involvement of the t(3;8) breakpoint region in the development of renal cell carcinoma suggested by loss of heterozygosity analysis. Genes Chromosomes Cancer. 1996 Jan;15(1):64–72. doi: 10.1002/(SICI)1098-2264(199601)15:1<64::AID-GCC9>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  35. van den Berg E., Dijkhuizen T., Oosterhuis J. W., Geurts van Kessel A., de Jong B., Störkel S. Cytogenetic classification of renal cell cancer. Cancer Genet Cytogenet. 1997 May;95(1):103–107. doi: 10.1016/s0165-4608(96)00289-0. [DOI] [PubMed] [Google Scholar]

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