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Hereditary kidney cancer syndromes

Toni K Choueiri, MD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD


Hereditary kidney cancer syndromes were originally described based upon clinical observations that defined the disease phenotype. Family studies and advances in molecular genetics have provided important insights into the molecular pathways underlying the pathogenesis of these syndromes, as well as new insights into sporadic renal cell carcinoma (RCC) [1,2]. Each of these syndromes has its own molecular alteration, and these are often reflected in distinctive histologic features and clinical course. Less than 5 percent of all RCC cases are thought to be due to a hereditary syndrome [3].

The inherited kidney cancer syndromes are summarized and reviewed here (table 1). Other topics provide more general discussions of RCC and its management. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma" and "Epidemiology, pathology, and pathogenesis of renal cell carcinoma" and "Prognostic factors in patients with renal cell carcinoma".)


Autosomal dominant polycystic kidney disease is a common disorder, occurring in approximately 1 in every 400 to 1000 live births. It is estimated that less than one-half of these cases are diagnosed during an individual's lifetime, since the disease is often clinically silent. (See "Genetics of autosomal dominant polycystic kidney disease and mechanisms of cyst growth" and "Course and treatment of autosomal dominant polycystic kidney disease" and "Renal manifestations of autosomal dominant polycystic kidney disease", section on 'Renal cancer'.)

The incidence of renal cell carcinoma (RCC) in patients with polycystic kidney disease does not appear to be increased compared with the general population [4,5]. However, the tumors are more often bilateral at presentation (12 versus 1 to 4 percent in sporadic RCC in the general population), multicentric (28 versus 6 percent), and sarcomatoid in type (33 versus 1 to 5 percent).


Hereditary papillary renal carcinoma (HPRC) is a familial cancer syndrome in which affected individuals are at risk for the development of type 1 papillary renal cell carcinomas [6].


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Literature review current through: May 2017. | This topic last updated: May 16, 2017.
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  1. Hwang JJ, Uchio EM, Linehan WM, Walther MM. Hereditary kidney cancer. Urol Clin North Am 2003; 30:831.
  2. Courtney KD, Choueiri TK. Optimizing recent advances in metastatic renal cell carcinoma. Curr Oncol Rep 2009; 11:218.
  3. Zbar B, Glenn G, Merino M, et al. Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. J Urol 2007; 177:461.
  4. Keith DS, Torres VE, King BF, et al. Renal cell carcinoma in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1994; 4:1661.
  5. Vogelzang NJ, Stadler WM. Kidney cancer. Lancet 1998; 352:1691.
  6. Zbar B, Tory K, Merino M, et al. Hereditary papillary renal cell carcinoma. J Urol 1994; 151:561.
  7. Dharmawardana PG, Giubellino A, Bottaro DP. Hereditary papillary renal carcinoma type I. Curr Mol Med 2004; 4:855.
  8. Schmidt LS, Nickerson ML, Angeloni D, et al. Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 2004; 172:1256.
  9. Herts BR, Coll DM, Novick AC, et al. Enhancement characteristics of papillary renal neoplasms revealed on triphasic helical CT of the kidneys. AJR Am J Roentgenol 2002; 178:367.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Alam NA, Bevan S, Churchman M, et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum Genet 2001; 68:1264.
  15. Pollard P, Wortham N, Barclay E, et al. Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 2005; 205:41.
  16. Ooi A, Wong JC, Petillo D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 2011; 20:511.
  17. Sudarshan S, Sourbier C, Kong HS, et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol 2009; 29:4080.
  18. 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.
  19. 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.
  20. Ylisaukko-oja SK, Kiuru M, Lehtonen HJ, et al. Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer 2006; 119:283.
  21. Wei MH, Toure O, Glenn GM, et al. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 2006; 43:18.
  22. Muller M, Ferlicot S, Guillaud-Bataille M, et al. Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. Clin Genet 2017.
  23. Sudarshan S, Pinto PA, Neckers L, Linehan WM. Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer. Nat Clin Pract Urol 2007; 4:104.
  24. 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.
  25. Vanharanta S, Buchta M, McWhinney SR, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 2004; 74:153.
  26. Ricketts C, Woodward ER, Killick P, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 2008; 100:1260.
  27. Shuch B, Agochukwu N, Ricketts CJ, et al. Vascular Endothelial Growth Factor Receptor-Targeted Therapy in Succinate Dehydrogenase C Kidney Cancer. J Clin Oncol 2016; 34:e76.
  28. Paik JY, Toon CW, Benn DE, et al. Renal carcinoma associated with succinate dehydrogenase B mutation: a new and unique subtype of renal carcinoma. J Clin Oncol 2014; 32:e10.
  29. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol 2009; 10:1199.
  30. 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.
  31. Hasumi H, Baba M, Hasumi Y, et al. Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome. Int J Urol 2016; 23:204.
  32. 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.
  33. 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.
  34. 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.
  35. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 2002; 26:1542.
  36. Houweling AC, Gijezen LM, Jonker MA, et al. Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer 2011; 105:1912.
  37. Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 2007; 175:1044.
  38. Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977; 113:1674.
  39. Welsch MJ, Krunic A, Medenica MM. Birt-Hogg-Dubé Syndrome. Int J Dermatol 2005; 44:668.
  40. Pavlovich CP, Grubb RL 3rd, Hurley K, et al. Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol 2005; 173:1482.
  41. Barrisford GW, Singer EA, Rosner IL, et al. Familial renal cancer: molecular genetics and surgical management. Int J Surg Oncol 2011; 2011:658767.
  42. 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.
  43. Lane BR, Aydin H, Danforth TL, et al. Clinical correlates of renal angiomyolipoma subtypes in 209 patients: classic, fat poor, tuberous sclerosis associated and epithelioid. J Urol 2008; 180:836.
  44. Bjornsson J, Short MP, Kwiatkowski DJ, Henske EP. Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol 1996; 149:1201.
  45. Woodward ER, Ricketts C, Killick P, et al. Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Clin Cancer Res 2008; 14:5925.
  46. Farley MN, Schmidt LS, Mester JL, et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol Cancer Res 2013; 11:1061.