Abstract
Renal cell carcinoma (RCC) is a heterogeneous disorder. A variety of histopathological subtypes occur, and the molecular mechanisms associated with these subtypes can differ. Only a small fraction of all RCC is accounted for by inherited cases (e.g. von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary leiomyomatosis renal cell cancer), but such cases can pose specific clinical management issues and offer opportunities for early cancer detection and prevention. Furthermore, inherited RCC syndromes have provided important paradigms to study the molecular basis of renal tumourigenesis. The identification of molecular mechanisms of carcinogenesis in inherited RCC syndromes should lead to novel approaches to personalized therapeutics.
References
1.
Lipworth L, Tarone RE, McLaughlin JK: The epidemiology of renal cell carcinoma. J Urol 2006;176:2353–2358.
[PubMed]
2.
Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Storkel S, van den Berg E, Zbar B: The Heidelberg classification of renal cell tumours. J Pathol 1997;183:131–133.
[PubMed]
3.
Maher ER: Von Hippel-Lindau disease. Curr Mol Med 2004;4:833–842.
[PubMed]
4.
Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, Wykoff CC, Maher ER, Harris AL, Ratcliffe PJ, Maxwell PH: HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 2002;1:459–468.
[PubMed]
5.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou FW, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng YK, Duan DSR, Dean M, Glavac D, Richards FM, Crossey PA, Ferguson-Smith MA, Lepaslier D, Chumakov I, Cohen D, Chinault AC, Maher ER, Linehan WM, Zbar B, Lerman MI: Identification of the von Hippel-Lindau disease tumor-suppressor gene. Science 1993;260:1317–1320.
[PubMed]
6.
Ong KR, Woodward ER, Killick P, Lim C, Macdonald F, Maher ER: Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat 2007;28:143–149.
[PubMed]
7.
Woodward ER, Eng C, McMahon R, Voutilainen R, Affara NA, Ponder BA, Maher ER: Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet 1997;67:1051–1056.
8.
Woodward ER, Skytte AB, Cruger DG, Maher ER: Population-based survey of cancer risks in chromosome 3 translocation carriers. Genes Chromosomes Cancer 2010;49:52–58.
[PubMed]
9.
Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER, European BHD Consortium: Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol 2009;10:1199–1206.
[PubMed]
10.
Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM: BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet 2008;45:321–331.
[PubMed]
11.
Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS: 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-Dube syndrome. Cancer Cell 2002;2:157–164.
[PubMed]
12.
Woodward ER, Ricketts C, Killick P, Gad S, Morris MR, Kavalier F, Hodgson SV, Giraud S, Bressac-de Paillerets B, Chapman C, Escudier B, Latif F, Richard S, Maher ER: Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Clin Cancer Res 2008;14:5925–5930.
[PubMed]
13.
Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Zbar B, 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.
[PubMed]
14.
Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406–410.
[PubMed]
15.
Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW 3rd, Cornelisse CJ, Devilee P, Devlin B: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 200;287:848–851.
16.
Astuti D, Douglas F, Lennard TW, Aligianis IA, Woodward ER, Evans DG, Eng C, Latif F, Maher ER: Germline SDHD mutation in familial phaeochromocytoma. Lancet 2001;357:1181–1182.
[PubMed]
17.
Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49–54.
[PubMed]
18.
Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C: The Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459–1466.
[PubMed]
19.
Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X, COMETE Network: Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003;63:5615–5621.
[PubMed]
20.
Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, Maher ER: Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008;100:1260–1262.
[PubMed]
21.
Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, Cole TR, Armstrong R, Kumar VK, Morrison PJ, Atkinson AB, Douglas F, Ball SG, Cook J, Srirangalingam U, Killick P, Kirby G, Aylwin S, Woodward ER, Evans DG, Hodgson SV, Murday V, Chew SL, Connell JM, Blundell TL, Macdonald F, Maher ER: Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 2010;31:41–51.
[PubMed]
22.
Rosser T, Panigrahy A, McClintock W: The diverse clinical manifestations of tuberous sclerosis complex: a review. Semin Pediatr Neurol 2006;13:27–36.
[PubMed]
23.
Yeung RS, Xiao GH, Jin F, Lee WC, Testa JR, Knudson AG: Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci USA 1994;91:11413–11416.
[PubMed]
24.
Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Höög A, Heath H 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C, Hobbs MR: HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 2002;32:676–680.
[PubMed]
25.
Rouprêt M, Yates DR, Comperat E, Cussenot O: Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (Lynch syndrome) tumor spectrum. Eur Urol 2008;54:1226–1236.
[PubMed]
26.
Maxwell PH, Wiesener MS, Chang GT-W, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliff PJ: The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271–275.
[PubMed]
27.
Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr: Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237–246.
[PubMed]
28.
Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E: Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005;7:77–85.
[PubMed]
29.
Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L: 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.
[PubMed]
30.
Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B: 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 USA 2006;103:15552–15557.
[PubMed]
31.
Brugarolas J, Kaelin WG Jr: Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 2004;6:7–10.
[PubMed]
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