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01-02-2011

Impact of Genetics on the Diagnosis and Treatment of Renal Cancer

Authors: Eric A. Singer, Gennady Bratslavsky, Lindsay Middelton, Ramaprasad Srinivasan, W. Marston Linehan

Published in: Current Urology Reports | Issue 1/2011

Abstract

Kidney cancer is a heterogeneous disease comprised of a number of histologic subtypes, each associated with unique genetic mutations, clinical features, and sensitivity to treatment. By examining families affected with the hereditary kidney cancer syndromes von Hippel-Lindau, hereditary papillary renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma, and Birt-Hogg-Dubé, researchers have been able to identify the genes responsible for these syndromes. This work has revealed that kidney cancer is fundamentally a metabolic disorder, and as such, novel targeted therapies specific to their molecular biology have been developed and employed in both the hereditary and sporadic forms of renal cell carcinoma.

Jemal A, Siegel R, Xu J, Ward E: Cancer Statistics, 2010. CA Cancer J Clin 2010, 60:277–300.CrossRefPubMed

Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr: Rising incidence of renal cell cancer in the United States. JAMA 1999, 281:1628–1631.CrossRefPubMed

Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK: Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2006, 98:1331–1334.CrossRefPubMed

Kovacs G, Akhtar M, Beckwith BJ, et al.: The Heidelberg classification of renal cell tumours. J Pathol 1997, 183:131–133.CrossRefPubMed

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

Linehan WM, Srinivasan R, Schmidt LS: The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol 2010, 7:277–285.CrossRefPubMed

Di Lorenzo G, Autorino R, Sternberg CN: Metastatic renal cell carcinoma: recent advances in the targeted therapy era. Eur Urol 2009, 56:959–971.CrossRefPubMed

• Rini BI: Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol 2009, 27:3225–3234. This is an excellent review of systemic therapy for metastatic RCC.CrossRefPubMed

•• Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2010, 28:893–901. This is the American Society of Clinical Oncology’s updated policy statement on the use of genetic testing in oncology.CrossRefPubMed

10.

Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 2005, 353:2477–2490.CrossRefPubMed

11.

Rosner I, Bratslavsky G, Pinto PA, Linehan WM: The clinical implications of the genetics of renal cell carcinoma. Urol Oncol 2009, 27:131–136.PubMed

12.

Walther MM, Lubensky IA, Venzon D, et al.: 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, 154:2010–2014.CrossRefPubMed

13.

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

14.

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

15.

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

16.

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

17.

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

18.

Ong KR, Woodward ER, Killick P, et al.: Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat 2007, 28:143–149.CrossRefPubMed

19.

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

20.

Kibel A, Iliopoulos O, DeCaprio JA, Kaelin WG Jr: Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science 1995, 269:1444–1446.CrossRefPubMed

21.

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 U S A 1997, 94:2156–2161.CrossRefPubMed

22.

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.CrossRefPubMed

23.

Kamura T, Koepp DM, Conrad MN, et al.: Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 1999, 284:657–661.CrossRefPubMed

24.

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.CrossRefPubMed

25.

Ohh M, Takagi Y, Aso T, et al.: Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. J Clin Invest 1999, 104:1583–1591.CrossRefPubMed

26.

Ohh M, Park CW, Ivan M, et al.: Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000, 2:423–427.CrossRefPubMed

27.

Stebbins CE, Kaelin WG Jr, Pavletich NP: Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science 1999, 284:455–461.CrossRefPubMed

28.

Nelson EC, Evans CP, Lara PN Jr: Renal cell carcinoma: current status and emerging therapies. Cancer Treat Rev 2007, 33:299–313.CrossRefPubMed

29.

Yagoda A, Petrylak D, Thompson S: Cytotoxic chemotherapy for advanced renal cell carcinoma. Urol Clin North Am 1993, 20:303–321.PubMed

30.

Singer EA, Bratslavsky G, Linehan WM, Srinivasan R: Targeted therapies for non-clear renal cell carcinoma. Target Oncol 2010, 5:119–129.CrossRefPubMed

31.

• Furge KA, MacKeigan JP, Teh BT: Kinase targets in renal-cell carcinomas: reassessing the old and discovering the new. Lancet Oncol 2010, 11:571–578. The authors review the use of molecularly targeted kinase inhibitors and identify promising new agents that may have activity against RCC.CrossRefPubMed

32.

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

33.

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 1997, 16:68–73.CrossRefPubMed

34.

Schmidt L, Junker K, Weirich G, et al.: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 1998, 58:1719–1722.PubMed

35.

Schmidt L, Junker K, Nakaigawa N, et al.: Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 1999, 18:2343–2350.CrossRefPubMed

36.

Choi JS, Kim MK, Seo JW, et al.: MET expression in sporadic renal cell carcinomas. J Korean Med Sci 2006, 21:672–677.CrossRefPubMed

37.

Dharmawardana PG, Giubellino A, Bottaro DP: Hereditary papillary renal carcinoma type I. Curr Mol Med 2004, 4:855–868.CrossRefPubMed

38.

Fischer J, Palmedo G, von Knobloch R, et al.: Duplication and overexpression of the mutant allele of the MET proto- oncogene in multiple hereditary papillary renal cell tumours. Oncogene 1998, 17:733–740.CrossRefPubMed

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.CrossRefPubMed

40.

Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 2001, 98:3387–3392.CrossRefPubMed

41.

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 Genet 2002, 30:406–410.CrossRefPubMed

42.

Grubb RL 3rd, Franks ME, Toro J, et al.: Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol 2007, 177:2074–2080.CrossRefPubMed

43.

Linehan WM, Pinto PA, Srinivasan R, et al.: Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics. Clin Cancer Res 2007, 13:671s–679s.CrossRefPubMed

44.

Isaacs JS, Jung YJ, Mole DR, et al.: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005, 8:143–153.CrossRefPubMed

45.

Linehan WM, Bratslavsky G, Pinto PA, et al.: Molecular diagnosis and therapy of kidney cancer. Annu Rev Med 2010, 61:329–343.CrossRefPubMed

46.

Srinivasan R, Linehan WM, Vaishampayan U, et al.: A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillary renal carcinoma (PRC). J Clin Oncol 2009, 27(May 20 Supplement):5103.

47.

Gordon MS, Hussey M, Nagle RB, et al.: Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol 2009, 27:5788–5793.CrossRefPubMed

48.

Choueiri TK, Plantade A, Elson P, et al.: Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 2008, 26:127–131.CrossRefPubMed

49.

Motzer RJ, Bacik J, Mariani T, et al.: Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002, 20:2376–2381.CrossRefPubMed

50.

National Institutes of Health: A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell carcinoma (HLRCC) or sporadic papillary renal cancer. Available at http://clinicaltrials.gov/ct2/show/NCT01130519. Accessed October 2010.

51.

Cheville JC, Lohse CM, Zincke H, et al.: Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 2003, 27:612–624.CrossRefPubMed

52.

Patard JJ, Leray E, Rioux-Leclercq N, et al.: Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005, 23:2763–2771.CrossRefPubMed

53.

Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 2002, 26:1542–1552.CrossRefPubMed

54.

Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 2002, 11:393–400.PubMed

55.

Nickerson ML, Warren MB, Toro JR, et al.: Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2002, 2:157–164.CrossRefPubMed

56.

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

57.

Schmidt LS, Nickerson ML, Warren MB, et al.: Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet 2005, 76:1023–1033.CrossRefPubMed

58.

Vocke CD, Yang Y, Pavlovich CP, et al.: High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé -associated renal tumors. J Natl Cancer Inst 2005, 97:931–935. (Published erratum appears in J Natl Cancer Inst 2005, 97:1096.)CrossRefPubMed

59.

Baba M, Hong SB, Sharma N, et al.: Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 2006, 103:15552–15557.CrossRefPubMed

60.

Hasumi H, Baba M, Hong SB, et al.: Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene 2008, 415:60–67.CrossRefPubMed

61.

Hasumi Y, Baba M, Ajima R, et al.: Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 2009, 106:18722–18727.CrossRefPubMed

62.

Baba M, Furihata M, Hong SB, et al.: Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst 2008, 100:140–154.CrossRefPubMed

63.

Walther MM, Choyke PL, Glenn G, 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, 161:1475–1479.CrossRefPubMed

64.

Herring JC, Enquist EG, Chernoff A, et al.: Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience. J Urol 2001, 165:777–781.CrossRefPubMed

65.

Boris R, Proano M, Linehan WM, et al.: Initial experience with robot assisted partial nephrectomy for multiple renal masses. J Urol 2009, 182:1280–1286.CrossRefPubMed

66.

Singer EA, Bratslavsky G: Management of locally recurrent kidney cancer. Curr Urol Rep 2010, 11:15–21.CrossRefPubMed

67.

Walther MM, Choyke PL, Weiss G, et al.: Parenchymal sparing surgery in patients with hereditary renal cell carcinoma. J Urol 1995, 153:913–916.CrossRefPubMed

68.

• Huang WC, Elkin EB, Levey AS, et al.: Partial nephrectomy versus radical nephrectomy in patients with small renal tumors—is there a difference in mortality and cardiovascular outcomes? J Urol 2009, 181:55–61. This article illustrates the importance of nephron-sparing surgery for renal tumors.CrossRefPubMed

69.

Linehan WM, Zbar B: Focus on kidney cancer. Cancer Cell 2004, 6:223–228. (Published erratum appears in Cancer Cell 2004, 223–228.)

70.

Pfaffenroth EC, Linehan WM: Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin Biol Ther 2008, 8:779–790.CrossRefPubMed

Title: Impact of Genetics on the Diagnosis and Treatment of Renal Cancer
Authors: Eric A. Singer
Gennady Bratslavsky
Lindsay Middelton
Ramaprasad Srinivasan
W. Marston Linehan
Publication date: 01-02-2011
Publisher: Current Science Inc.
Published in: Current Urology Reports / Issue 1/2011
Print ISSN: 1527-2737
Electronic ISSN: 1534-6285
DOI: https://doi.org/10.1007/s11934-010-0156-y

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Impact of Genetics on the Diagnosis and Treatment of Renal Cancer

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