Genetic Kidney Cancer Syndromes

Restricted access

Hereditary forms of renal cell carcinoma (RCC) have yielded clues regarding the molecular pathogenesis of sporadic RCC. The discovery of germline mutations in chromatin-modulating enzymes also defined a new hereditary RCC syndrome. Although histologically distinct RCC subtypes exist, emerging themes shared between hereditary and sporadic RCC include dysregulation of the von Hippel-Lindau tumor suppressor protein/hypoxia inducible factor axis, defective ciliogenesis, and aberrant tumor metabolism. This article describes the most common hereditary RCC syndromes and associated extrarenal manifestations. Recent evidence supports developing screening guidelines for early-onset RCC to identify persons with germline mutations in the absence of secondary clinical manifestations.

Correspondence: Eric Jonasch, MD, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1374, Houston, TX 77030. E-mail: ejonasch@mdanderson.org
  • 1.

    Shuch B, Vourganti S, Ricketts CJ. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 2013.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ricketts CJ, Forman JR, Rattenberry E. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 2010;31:4151.

    • Search Google Scholar
    • Export Citation
  • 3.

    Latif F, Tory K, Gnarra J. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:13171320.

  • 4.

    Prowse AH, Webster AR, Richards FM. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am J Hum Genet 1997;60:765771.

    • Search Google Scholar
    • Export Citation
  • 5.

    Latif F, Duh FM, Gnarra J. von Hippel-Lindau syndrome: cloning and identification of the plasma membrane Ca(++)-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region. Cancer Res 1993;53:861867.

    • Search Google Scholar
    • Export Citation
  • 6.

    Cockman ME, Masson N, Mole DR. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000;275:2573325741.

    • Search Google Scholar
    • Export Citation
  • 7.

    Maxwell PH, Wiesener MS, Chang GW. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271275.

    • Search Google Scholar
    • Export Citation
  • 8.

    Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721732.

  • 9.

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

  • 10.

    Xu J, Li H, Wang B. VHL inactivation induces HEF1 and Aurora kinase A. J Am Soc Nephrol 2010;21:20412046.

  • 11.

    Binderup ML, Bisgaard ML, Harbud V. Von Hippel-Lindau Disease (vHL). National Clinical Guideline for Diagnosis and Surveillance in Denmark. 3rd ed. Dan Med J 2013;60:B4763.

    • Search Google Scholar
    • Export Citation
  • 12.

    Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet 2011;19:617623.

  • 13.

    Jonasch E, McCutcheon IE, Waguespack SG. Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann Oncol 2011;22:26612666.

    • Search Google Scholar
    • Export Citation
  • 14.

    Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:255265.

    • Search Google Scholar
    • Export Citation
  • 15.

    Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274293.

  • 16.

    Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:13451356.

  • 17.

    Bissler JJ, Kingswood JC, Radzikowska E. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013;381:817824.

    • Search Google Scholar
    • Export Citation
  • 18.

    Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991;66:792796.

  • 19.

    Pilarski R, Burt R, Kohlman W. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 2013;105:16071616.

    • Search Google Scholar
    • Export Citation
  • 20.

    Sun H, Lesche R, Li DM. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A 1999;96:61996204.

    • Search Google Scholar
    • Export Citation
  • 21.

    Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499:4349.

  • 22.

    Tan MH, Mester JL, Ngeow J. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012;18:400407.

  • 23.

    Schmidt L, Duh FM, Chen F. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 1997;16:6873.

    • Search Google Scholar
    • Export Citation
  • 24.

    Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol 2010;7:277285.

  • 25.

    Zhuang Z, Park WS, Pack S. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 1998;20:6669.

    • Search Google Scholar
    • Export Citation
  • 26.

    Ornstein DK, Lubensky IA, Venzon D. Prevalence of microscopic tumors in normal appearing renal parenchyma of patients with hereditary papillary renal cancer. J Urol 2000;163:431433.

    • Search Google Scholar
    • Export Citation
  • 27.

    Choueiri TK, Vaishampayan U, Rosenberg JE. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 2013;31:181186.

    • Search Google Scholar
    • Export Citation
  • 28.

    Herring JC, Enquist EG, Chernoff A. Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience. J Urol 2001;165:777781.

    • Search Google Scholar
    • Export Citation
  • 29.

    Toro JR, Nickerson ML, Wei MH. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003;73:95106.

    • Search Google Scholar
    • Export Citation
  • 30.

    Tomlinson IP, Alam NA, Rowan AJ. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406410.

    • Search Google Scholar
    • Export Citation
  • 31.

    Ashrafian H, O’Flaherty L, Adam J. Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer Res 2010;70:91539165.

    • Search Google Scholar
    • Export Citation
  • 32.

    Pollard PJ, Spencer-Dene B, Shukla D. Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 2007;11:311319.

    • Search Google Scholar
    • Export Citation
  • 33.

    Yamasaki T, Tran TA, Oz OK. Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. Nat Rev Urol 2011;8:165171.

    • Search Google Scholar
    • Export Citation
  • 34.

    Smit DL, Mensenkamp AR, Badeloe S. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet 2011;79:4959.

    • Search Google Scholar
    • Export Citation
  • 35.

    Ricketts CJ, Shuch B, Vocke CD. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol 2012;188:20632071.

    • Search Google Scholar
    • Export Citation
  • 36.

    Selak MA, Armour SM, MacKenzie ED. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005;7:7785.

    • Search Google Scholar
    • Export Citation
  • 37.

    Pollard PJ, Briere JJ, Alam NA. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005;14:22312239.

    • Search Google Scholar
    • Export Citation
  • 38.

    Menko FH, van Steensel MA, Giraud S. Birt-Hogg-Dube syndrome: diagnosis and management. Lancet Oncol 2009;10:11991206.

  • 39.

    Luijten MN, Basten SG, Claessens T. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum Mol Genet 2013;22:43834397.

  • 40.

    Houweling AC, Gijezen LM, Jonker MA. Renal cancer and pneumothorax risk in Birt-Hogg-Dube syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer 2011;105:19121919.

    • Search Google Scholar
    • Export Citation
  • 41.

    Stamatakis L, Metwalli AR, Middelton LA. Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 2013;12:397402.

  • 42.

    Zbar B, Alvord WG, Glenn G. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002;11:393400.

    • Search Google Scholar
    • Export Citation
  • 43.

    Baba M, Furihata M, Hong SB. 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;100:140154.

    • Search Google Scholar
    • Export Citation
  • 44.

    Gijezen LM, Vernooij M, Martens H. Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dube syndrome: a double-blind placebo-controlled randomized split-face trial. PLoS One 2014;9:e99071.

    • Search Google Scholar
    • Export Citation
  • 45.

    Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2012;44:751759.

  • 46.

    Yu H, Pak H, Hammond-Martel I. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc Natl Acad Sci U S A 2014;111:285290.

    • Search Google Scholar
    • Export Citation
  • 47.

    Popova T, Hebert L, Jacquemin V. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 2013;92:974980.

  • 48.

    Voss MH, Hakimi AA, Pham CG. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res 2014;20:19551964.

    • Search Google Scholar
    • Export Citation
  • 49.

    Linehan WM. Evaluation and screening for hereditary renal cell cancers. Can Urol Assoc J 2013;7:324325.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 396 294 12
PDF Downloads 274 258 17
EPUB Downloads 0 0 0