Skip to main content

Molecular Genetics in Inherited Renal Cell Carcinoma: Identification of Targets in the Hereditary Syndromes

  • Chapter
  • 768 Accesses

Abstract

An estimated 12,000 people will die of kidney cancer this year. With the increased use of axial abdominal imaging, kidney tumors are being diagnosed at earlier stages, often incidentally while the patient is still asymptomatic. While extirpative surgery is most often curative in tumors restricted to the kidney, treatment of metastatic disease has proven to be a formidable challenge. As our understanding of the genetic basis of kidney cancer increases, advances in molecular therapies offer new approaches to treatment. Understanding the cellular mechanisms of oncogenesis have the potential to change the face of renal cancer therapy.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55(1):10–30.

    Article  PubMed  Google Scholar 

  2. Surveillance, Epidemiology, and End Results Program, 1992.

    Google Scholar 

  3. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820–823.

    Article  PubMed  Google Scholar 

  4. Knudson AG Jr, Strong LC. Mutation and cancer: a model for Wilms’ tumor of the kidney. J Natl Cancer Inst 1972;48:313–324.

    PubMed  Google Scholar 

  5. Cohen AJ, Li FP, Berg S, et al. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med 1979;301:592–595.

    PubMed  CAS  Google Scholar 

  6. Zbar B, Brauch H, Talmadge C, Linehan WM. Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 1987;327:721–724.

    Article  PubMed  CAS  Google Scholar 

  7. Seizinger BR, Rouleau GA, Ozelius LJ, et al. Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 1988;332(6161):268–269.

    Article  PubMed  CAS  Google Scholar 

  8. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol 2003;170: 2163–2172.

    Article  PubMed  CAS  Google Scholar 

  9. Lonser R, Glenn G, Walther MM, et al. von Hippel-Lindau disease. Lancet 2003;361(9374): 2059–2067.

    Article  PubMed  CAS  Google Scholar 

  10. Maher ER, Yates JRW, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med, in press.

    Google Scholar 

  11. Walther MM, Lubensky IA, Venzon D, Zbar B, Linehan WM. Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: Clinical implications. J Urol 1995;154:2010–2015.

    Article  PubMed  CAS  Google Scholar 

  12. Choyke PL, Glenn GM, Walther MM, et al. The natural history of renal lesions in von Hippel-Lindau disease: a serial ct study in 28 patients. Am J Roentgenol 1992;159(6):1229–1234.

    CAS  Google Scholar 

  13. Lonser R, Glenn G, Walther MM, et al. von Hippel-Lindau disease. Lancet 2003; 361(9374):2059–2067.

    Article  PubMed  CAS  Google Scholar 

  14. Tory K, Brauch H, Linehan WM, et al. Specific genetic change in tumors associated with von Hippel-Lindau disease. J Natl Cancer Inst 1989;81:1097–1101.

    Article  PubMed  CAS  Google Scholar 

  15. Seizinger BR, Rouleau GA, Ozelius LJ, et al. Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 1988;332:268–269.

    Article  PubMed  CAS  Google Scholar 

  16. Lerman MI, Latif F, Glenn GM, et al. Isolation and regional localization of a large collection (2,000) of single copy DNA fragments on human chromosome 3 for mapping and cloning tumor suppressor genes. Hum Genet 1991;86:567–577.

    Article  PubMed  CAS  Google Scholar 

  17. Hosoe S, Brauch H, Latif F, et al. Localization of the von Hippel-Lindau disease gene to a small region of chromosome 3. Genom 1990;8:634–640.

    Article  CAS  Google Scholar 

  18. Latif F, Tory K, Gnarra JR, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317–1320.

    Article  PubMed  CAS  Google Scholar 

  19. Whaley JM, Naglich J, Gelbert L, et al. Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to von Hippel-Lindau aberrations in sporadic renal cell carcinoma. Am J Hum Genet 1994;55:1092–1102.

    PubMed  CAS  Google Scholar 

  20. Chen F, Kishida T, Yao M, et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlation with phenotype. Hum Mutat 1995;5:66–75.

    Article  PubMed  CAS  Google Scholar 

  21. Zbar B, Kishida T, Chen F, et al. Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe and Japan. Hum Mutat 1996;8:348–357.

    Article  PubMed  CAS  Google Scholar 

  22. Maranchie JK, Afonso A, Albert P, et al. Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. Hum Mutat 2004;23(1):40–46.

    Article  PubMed  CAS  Google Scholar 

  23. Stolle C, Glenn GM, Zbar B, et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998;12(6):417–423.

    Article  PubMed  CAS  Google Scholar 

  24. Gnarra JR, Tory K, Weng Y, et al. Mutation of the VHL tumour suppressor gene in renal carcinoma. Nat Gen 1994;7:85–90.

    Article  CAS  Google Scholar 

  25. Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA 1994;91:9700–9704.

    Article  PubMed  CAS  Google Scholar 

  26. Linehan WM, Lerman MI, Zbar B. Identification of the VHL gene: its role in renal carcinoma. JAMA 1995;273(7):564–570.

    Article  PubMed  CAS  Google Scholar 

  27. Lubensky IA, Gnarra JR, Bertheau P, Walther MM, Linehan WM, Zhuang Z. Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients. Am J Pathol 1996;149(6):2089–2094.

    PubMed  CAS  Google Scholar 

  28. Lee Y-S, Vortmeyer AO, Lubensky IA, et al. Co-expression of erythropoietin and erythropoietin receptor in von Hippel-Lindau disease-associated renal cysts and renal cell carcinoma. Clin Cancer Res 2005;11(3):1059–1064.

    PubMed  CAS  Google Scholar 

  29. Duan DR, Humphrey JS, Chen DYT, et al. Characterization of the VHL tumor suppressor gene product: Localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci USA 1995;92:6459–6463.

    Article  PubMed  CAS  Google Scholar 

  30. Duan DR, Pause A, Burgess WH, et al. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science 1995;269:1402–1406.

    Article  PubMed  CAS  Google Scholar 

  31. Iliopoulos O, Jiang C, Levy AP, Kaelin WG, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 1996;93(20):10595–10599.

    Article  PubMed  CAS  Google Scholar 

  32. Pause A, Lee S, Worrell RA, et al. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci USA 1997;94(6):2156–2161.

    Article  PubMed  CAS  Google Scholar 

  33. Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 1996;56:2299–2301.

    PubMed  CAS  Google Scholar 

  34. Cockman ME, Masson N, Mole DR, et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000;275(33):25733–25741.

    Article  PubMed  CAS  Google Scholar 

  35. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107(1):43–54.

    Article  PubMed  CAS  Google Scholar 

  36. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468–472.

    Article  PubMed  CAS  Google Scholar 

  37. Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD. The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002;1:247–255.

    Article  PubMed  CAS  Google Scholar 

  38. Zbar B, Tory K, Merino M, et al. Hereditary papillary renal cell carcinoma. J Urol 1994;151: 561–566.

    PubMed  CAS  Google Scholar 

  39. Zbar B, Glenn GM, Lubensky IA, et al. Hereditary papillary renal cell carcinoma: Clinical studies in 10 families. J Urol 1995;153:907–912.

    Article  PubMed  CAS  Google Scholar 

  40. Ornstein DK, Lubensky IA, Venzon D, Zbar B, Linehan WM, Walther MM. Prevalence of microscopic tumors in normal appearing renal parenchyma from patients with hereditary papillary renal cancer. J Urol 2000;163(2):431–433.

    Article  PubMed  CAS  Google Scholar 

  41. Lubensky IA, Schmidt L, Zhuang Z, et al. Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 1999;155(2):517–526.

    PubMed  CAS  Google Scholar 

  42. Choyke PL, Walther MM, Glenn GM, et al. Imaging features of hereditary papillary renal cancers. J Comput Assist Tomogr 1997;21(1997):737–741.

    Article  PubMed  CAS  Google Scholar 

  43. Schmidt L, Duh F-M, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Gen 1997;16(May):68–73.

    Article  CAS  Google Scholar 

  44. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 1991;251(4995):802–804.

    Article  PubMed  CAS  Google Scholar 

  45. Zhang YW, Vande Woude GF. HGF/SF-met signaling in the control of branching morphogenesis and invasion. J Cell Biochem 2003;88(2):408–417.

    Article  PubMed  CAS  Google Scholar 

  46. Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977;113(12):1674–1677.

    Article  PubMed  CAS  Google Scholar 

  47. Toro J, Duray PH, Glenn GM, et al. Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999;135(10):1195–1202.

    Article  PubMed  CAS  Google Scholar 

  48. Binet O, Robin J, Vicart M, Ventura G, Beltzer-Garelly E. Fibromes Perifolliculaires polypose colique familaile pneumothorax spontanes familiaux. Ann Dermotol Venereol 1986;113:928–930.

    Google Scholar 

  49. Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 2000;43:1120–1122.

    Article  PubMed  CAS  Google Scholar 

  50. Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F. Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome. Int J Dermatol 1996;35(5):365–367.

    Article  PubMed  CAS  Google Scholar 

  51. Hornstein OP. Generalized dermal perifollicular fibromas with polyps of the colon. Hum Genet 1976;33(2):193–197.

    Article  PubMed  CAS  Google Scholar 

  52. Zbar B, Alvord G, Glenn G, et al. Risk of renal and colon neoplasms and spontaneous pneumothorax in the Birt Hogg Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002;11(4):393–400.

    PubMed  Google Scholar 

  53. Pavlovich CP, Hewitt S, Walther MM, et al. Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol 2002;26(12):1542–1552.

    Article  PubMed  Google Scholar 

  54. Schmidt LS, Warren MB, Nickerson ML, et al. Birt Hogg Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 2001;69:876–882.

    Article  PubMed  CAS  Google Scholar 

  55. Vocke CD, Yang Y, Pavlovich CP, et al. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal tumors. J Natl Cancer Inst 2005;97(12):931–935.

    Article  PubMed  CAS  Google Scholar 

  56. Warren MB; Torres-Cabala CA, Turner ML, et al. Expression of Birt-Hogg-Dube gene mRNA in normal and neoplastic human tissues. Mod Pathol 2004;17(8):998–1011.

    Article  PubMed  CAS  Google Scholar 

  57. Launonen V, Vierimaa O, Kiuru M, et al. Inherited Susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 2001;98(6):3387–3382.

    Article  PubMed  CAS  Google Scholar 

  58. Alam NA, Bevan S, Churchman M, et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum Genet 2001;68(5):1264–1269.

    Article  PubMed  CAS  Google Scholar 

  59. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Gen 2002;30(4):406–410.

    Article  CAS  Google Scholar 

  60. Isaacs JT, Jung YJ, Mole DR, et al. HIF overexpression correlates with biallilic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005;8(2):143–153.

    Article  PubMed  CAS  Google Scholar 

  61. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003;73(1):95–106.

    Article  PubMed  CAS  Google Scholar 

  62. Wei M-H, Toure O, Glenn GM, et al. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 2005.

    Google Scholar 

  63. Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell carcinoma. J Urol 1969;101:297–301.

    PubMed  CAS  Google Scholar 

  64. Clayman RV, Kavoussi LR, Soper NJ, et al. Laparoscopic nephrectomy: initial case report. J Urol 1991;146:278–282.

    PubMed  CAS  Google Scholar 

  65. Butler BP, Novick AC, Miller DP, Campbell SA, Licht MR. Management of small unilateral renal cell carcinomas: radical versus nephron-sparing surgery. Urology 1995;45:34–41.

    Article  PubMed  CAS  Google Scholar 

  66. Lerner SE, Hawkins CA, Blute ML, et al. Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol 1996;155:1868–1873.

    Article  PubMed  CAS  Google Scholar 

  67. Walther MM, Choyke PL, Glenn GM, et al. Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol 1999;161(5):1475–1479.

    Article  PubMed  CAS  Google Scholar 

  68. Hwang JJ, Walther MM, Pautler SE, et al. Radio frequency ablation of small renal tumors: intermediate results. J Urol 2004;171(5):1814–1818.

    Article  PubMed  CAS  Google Scholar 

  69. Srinivasan R, Linehan WM. Targeted for destruction: the molecular basis for development of novel therapeutic strategies in renal cell cancer. J Clin Oncol 2005;23(3):410–412.

    Article  PubMed  CAS  Google Scholar 

  70. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344(14):1052–1056.

    Article  PubMed  CAS  Google Scholar 

  71. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344(14):1038–1042.

    Article  PubMed  CAS  Google Scholar 

  72. Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 2004;64(4):1475–1482.

    Article  PubMed  CAS  Google Scholar 

  73. Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003;1(3):E83.

    Article  PubMed  Google Scholar 

  74. Seagroves T, Johnson RS. Two HIFs may be better than one. Cancer Cell 2002;1:211–213.

    Article  PubMed  CAS  Google Scholar 

  75. Linehan WM, Vasselli J, Srinivasan R, et al. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res 2004;10(18):6282S–6289S.

    Article  PubMed  CAS  Google Scholar 

  76. Linehan WM, Zbar B. Focus on kidney cancer. Cancer Cell 2004;6(3):223–228.

    Article  PubMed  CAS  Google Scholar 

  77. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349(5):427–434.

    Article  PubMed  CAS  Google Scholar 

  78. Ratain MJ, Flaherty KT, Stadler WM, et al. Preliminary antitumor activity of BAY 43-9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT). J Clin Oncol (Meeting Abstracts) 2004;22(14 suppl):382.

    Google Scholar 

  79. Bennasroune A, Gardin A, Aunis D, Cremel G, Hubert P. Tyrosine kinase receptors as attractive targets of cancer therapy. Crit Rev Oncol/Hematol 2004:50(1):23–38.

    Article  Google Scholar 

  80. Ciardiello F, Caputo R, Damiano V, et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 2003;9(4):1546–1556.

    PubMed  CAS  Google Scholar 

  81. Hainsworth JD, Sosman JA, Spigel DR, et al. Phase II trial of bevacizumab and erlotinib in patients with metastatic renal carcinoma (RCC). J Clin Oncol (Meeting Abstracts) 2004; 22(14 suppl):382–38b.

    Google Scholar 

  82. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers L. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 2002;277(33):29936–29944.

    Article  PubMed  CAS  Google Scholar 

  83. Yamazaki K, Sakamoto M, Ohta T, Kanai Y, Ohki M, Hirohashi S. Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene 2003;22(6):847–852.

    Article  PubMed  CAS  Google Scholar 

  84. Lin ZH, Han EM, Lee ES, et al. A distinct expression pattern and point mutation of c-kit in papillary renal cell carcinomas. Mod Pathol 2004.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Dhanani, N., Vocke, C., Bratslavsky, G., Linehan, W.M. (2008). Molecular Genetics in Inherited Renal Cell Carcinoma: Identification of Targets in the Hereditary Syndromes. In: Bukowski, R.M., Novick, A.C. (eds) Clinical Management of Renal Tumors. Humana Press. https://doi.org/10.1007/978-1-60327-149-3_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-149-3_6

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-251-3

  • Online ISBN: 978-1-60327-149-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics