Hereditary renal cell carcinoma (RCC) has been estimated to account for 5% to 8% of all RCC cases, and extrarenal manifestations may present as early as 3 years of age (Table 1).1,2 RCC is a diverse set of cancers that originate from the renal parenchyma. Histologic classifications include clear cell, papillary, chromophobe, and translocation; rare subtypes include renal medullary and collecting duct. Hereditary familial RCC syndromes have yielded clues regarding the molecular pathogenesis of sporadic RCC and have served as a framework for the development of targeted therapies. With diverse presentations and incomplete penetrance of RCC, establishing screening guidelines for detecting early-onset RCC may help identify persons with germline mutations who have an increased risk of developing RCC.
Shuch B, Vourganti S, Ricketts CJ et al.. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 2013.
Ricketts CJ, Forman JR, Rattenberry E et al.. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat 2010;31:41–51.
Latif F, Tory K, Gnarra J et al.. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317–1320.
Prowse AH, Webster AR, Richards FM et al.. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am J Hum Genet 1997;60:765–771.
Latif F, Duh FM, Gnarra J et al.. 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;53:861–867.
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;275:25733–25741.
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.
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.
Binderup ML, Bisgaard ML, Harbud V et al.. Von Hippel-Lindau Disease (vHL). National Clinical Guideline for Diagnosis and Surveillance in Denmark. 3rd ed. Dan Med J 2013;60:B4763.
Jonasch E, McCutcheon IE, Waguespack SG et al.. Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease. Ann Oncol 2011;22:2661–2666.
Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:255–265.
Bissler JJ, Kingswood JC, Radzikowska E et al.. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013;381:817–824.
Pilarski R, Burt R, Kohlman W et al.. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 2013;105:1607–1616.
Sun H, Lesche R, Li DM et al.. 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;96:6199–6204.
Tan MH, Mester JL, Ngeow J et al.. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012;18:400–407.
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.
Zhuang Z, Park WS, Pack S et al.. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 1998;20:66–69.
Ornstein DK, Lubensky IA, Venzon D et al.. Prevalence of microscopic tumors in normal appearing renal parenchyma of patients with hereditary papillary renal cancer. J Urol 2000;163:431–433.
Choueiri TK, Vaishampayan U, Rosenberg JE et al.. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 2013;31:181–186.
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.
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;73:95–106.
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.
Ashrafian H, O’Flaherty L, Adam J et al.. Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer Res 2010;70:9153–9165.
Pollard PJ, Spencer-Dene B, Shukla D et al.. Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 2007;11:311–319.
Yamasaki T, Tran TA, Oz OK et al.. Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. Nat Rev Urol 2011;8:165–171.
Smit DL, Mensenkamp AR, Badeloe S et al.. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet 2011;79:49–59.
Ricketts CJ, Shuch B, Vocke CD et al.. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol 2012;188:2063–2071.
Selak MA, Armour SM, MacKenzie ED et al.. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005;7:77–85.
Pollard PJ, Briere JJ, Alam NA et al.. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005;14:2231–2239.
Houweling AC, Gijezen LM, Jonker MA et al.. 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;105:1912–1919.
Stamatakis L, Metwalli AR, Middelton LA et al.. Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 2013;12:397–402.
Zbar B, Alvord WG, Glenn G et al.. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002;11:393–400.
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.
Gijezen LM, Vernooij M, Martens H et al.. 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.
Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A et al.. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2012;44:751–759.
Yu H, Pak H, Hammond-Martel I et al.. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc Natl Acad Sci U S A 2014;111:285–290.
Popova T, Hebert L, Jacquemin V et al.. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet 2013;92:974–980.
Voss MH, Hakimi AA, Pham CG et al.. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res 2014;20:1955–1964.