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VHL gene mutations in renal cell carcinoma: Role as a biomarker of disease outcome and drug efficacy

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Abstract

The therapeutic landscape for renal cell carcinoma (RCC) has changed drastically over the past several years with the emergence of molecularly targeted therapies. With previous prognostic and predictive tools based on studies of patients treated with cytokine therapies, confirmation of these prior methods and discovery of new markers in this new era of targeted therapy are of great importance. Alteration of the von Hippel-Lindau gene (VHL) by mutation, loss of heterozygosity, and promoter methylation has been found to be important to RCC pathogenesis. In this review, we discuss the potential role of VHL mutation as a prognostic and predictive marker for RCC.

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References and Recommended Reading

  1. Jemal A, Siegel R, Ward E, et al.: Cancer statistics, 2008. CA Cancer J Clin 2008, 58:71–96.

    Article  PubMed  Google Scholar 

  2. Motzer RJ, Russo P: Systemic therapy for renal cell carcinoma. J Urol 2000, 163:408–417.

    Article  PubMed  CAS  Google Scholar 

  3. Bukowski RM: Cytokine therapy for metastatic renal cell carcinoma. Semin Urol Oncol 2001, 19:148–154.

    PubMed  CAS  Google Scholar 

  4. Motzer RJ, Mazumdar M, Bacik J, et al.: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999, 17:2530–2540.

    PubMed  CAS  Google Scholar 

  5. Cowey C, Rathmell WK: Using molecular biology to develop drugs for renal cell carcinoma. Expert Opin Drug Discov 2008, 3:311–327.

    Article  CAS  Google Scholar 

  6. Kaelin WG Jr: The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res 2007, 13(2 Pt 2):680s–684s.

    Article  PubMed  CAS  Google Scholar 

  7. Motzer RJ, Hutson TE, Tomczak P, et al.: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007, 356:115–124.

    Article  PubMed  CAS  Google Scholar 

  8. Escudier B, Eisen T, Stadler WM, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007, 356:125–134.

    Article  PubMed  CAS  Google Scholar 

  9. Hudes G, Carducci M, Tomczak P, et al.: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007, 356:2271–2281.

    Article  PubMed  CAS  Google Scholar 

  10. Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 2003, 361:2059–2067.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Iliopoulos O, Levy AP, Jiang C, et al.: Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A 1996, 93:10595–10599.

    Article  PubMed  CAS  Google Scholar 

  13. Iwai K, Yamanaka K, Kamura T, et al.: Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A 1999, 96:12436–12441.

    Article  PubMed  CAS  Google Scholar 

  14. Maxwell PH, Wiesener MS, Chang GW, et al.: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999, 399:271–275.

    Article  PubMed  CAS  Google Scholar 

  15. Wiesener MS, Munchenhagen PM, Berger I, et al.: Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas. Cancer Res 2001, 61:5215–5222.

    PubMed  CAS  Google Scholar 

  16. Iliopoulos O, Kibel A, Gray S, et al.: Tumour suppression by the human von Hippel-Lindau gene product. Nat Med 1995, 1:822–826.

    Article  PubMed  CAS  Google Scholar 

  17. Chen F, Kishida T, Duh FM, et al.: Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. Cancer Res 1995, 55:4804–4807.

    PubMed  CAS  Google Scholar 

  18. 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 

  19. Friedrich CA: Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet 2001, 10:763–767.

    Article  PubMed  CAS  Google Scholar 

  20. Hacker KE, Lee CM, Rathmell WK: VHL type 2B mutations retain VBC form and function. PLoS ONE 2008, 3:e3801.

    Article  PubMed  Google Scholar 

  21. Li L, Zhang L, Zhang X, et al.: Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol 2007, 27:5381–5392.

    Article  PubMed  CAS  Google Scholar 

  22. Foster K, Prowse A, van den Berg A, et al.: Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 1994, 3:2169–2173.

    Article  PubMed  CAS  Google Scholar 

  23. Gnarra JR, Tory K, Weng Y, et al.: Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 1994, 7:85–90.

    Article  PubMed  CAS  Google Scholar 

  24. Shuin T, Kondo K, Torigoe S, et al.: Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res 1994, 54:2852–2855.

    PubMed  CAS  Google Scholar 

  25. Nickerson ML, Jaeger E, Shi Y, et al.: Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008, 14:4726–4734.

    Article  PubMed  CAS  Google Scholar 

  26. 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 U S A 1994, 91:9700–9704.

    Article  PubMed  CAS  Google Scholar 

  27. Clifford SC, Prowse AH, Affara NA, et al.: Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer 1998, 22:200–209.

    Article  PubMed  CAS  Google Scholar 

  28. Dulaimi E, Ibanez de Caceres I, Uzzo RG, et al.: Promoter hypermethylation profile of kidney cancer. Clin Cancer Res 2004, 10(12 Pt 1):3972–3979.

    Article  PubMed  CAS  Google Scholar 

  29. Brauch H, Weirich G, Brieger J, et al.: VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res 2000, 60:1942–1948.

    PubMed  CAS  Google Scholar 

  30. Schraml P, Struckmann K, Hatz F, et al.: VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma. J Pathol 2002, 196:186–193.

    Article  PubMed  CAS  Google Scholar 

  31. Patard JJ, Fergelot P, Karakiewicz PI, et al.: Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma. Int J Cancer 2008, 123:395–400.

    Article  PubMed  CAS  Google Scholar 

  32. Yao M, Yoshida M, Kishida T, et al.: VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. J Natl Cancer Inst 2002, 94:1569–1575.

    PubMed  CAS  Google Scholar 

  33. Kondo K, Yao M, Yoshida M, et al.: Comprehensive mutational analysis of the VHL gene in sporadic renal cell carcinoma: relationship to clinicopathological parameters. Genes Chromosomes Cancer 2002, 34:58–68.

    Article  PubMed  CAS  Google Scholar 

  34. Smits KM, Schouten LJ, van Dijk BA, et al.: Genetic and epigenetic alterations in the von hippel-lindau gene: the influence on renal cancer prognosis. Clin Cancer Res 2008, 14:782–787.

    Article  PubMed  CAS  Google Scholar 

  35. Gimenez-Bachs JM, Salinas-Sanchez AS, Sanchez-Sanchez F, et al.: Determination of vhl gene mutations in sporadic renal cell carcinoma. Eur Urol 2006, 49:1051–1057.

    Article  PubMed  CAS  Google Scholar 

  36. Upton MP, Parker RA, Youmans A, et al.: Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother 2005, 28:488–495.

    Article  PubMed  CAS  Google Scholar 

  37. Kim JH, Jung CW, Cho YH, et al.: Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma. Oncol Rep 2005, 13:859–864.

    PubMed  CAS  Google Scholar 

  38. Choueiri TK, Vaziri SA, Jaeger E, et al.: von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J Urol 2008, 180:860–865; discussion 865–866.

    Article  PubMed  CAS  Google Scholar 

  39. Rini BI, Jaeger E, Weinberg V, et al.: Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status. BJU Int 2006, 98:756–762.

    Article  PubMed  CAS  Google Scholar 

  40. Gad S, Sultan-Amar V, Meric JB, et al.: Somatic von Hippel-Lindau (VHL) gene analysis and clinical outcome under antiangiogenic treatment in metastatic renal cell carcinoma: preliminary results. Targeted Oncol 2007, 2:3–6.

    Article  Google Scholar 

  41. Cho D, Signoretti S, Regan M, et al.: The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res 2007, 13(2 Pt 2):758s–763s.

    Article  PubMed  CAS  Google Scholar 

  42. Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004, 350:2129–2139.

    Article  PubMed  CAS  Google Scholar 

  43. Carmeliet P: VEGF as a key mediator of angiogenesis in cancer. Oncology 2005, 69(Suppl 3):4–10.

    Article  PubMed  CAS  Google Scholar 

  44. Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007, 357:2666–2676.

    Article  PubMed  CAS  Google Scholar 

  45. Hurwitz H, Fehrenbacher L, Novotny W, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335–2342.

    Article  PubMed  CAS  Google Scholar 

  46. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008, 359:378–390.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to W. Kimryn Rathmell.

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Cowey, C.L., Rathmell, W.K. VHL gene mutations in renal cell carcinoma: Role as a biomarker of disease outcome and drug efficacy. Curr Oncol Rep 11, 94–101 (2009). https://doi.org/10.1007/s11912-009-0015-5

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