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Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)


[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2015, about 61,560 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to more than 14,080 deaths.[1] This cancer accounts for about 4% of all the adult malignancies. The male-to-female ratio is 1.5:1.[2] RCC is distinct from kidney cancer that involves the renal pelvis or renal medulla, and it only applies to cancer that forms in the lining of the kidney bed (i.e., in the renal tubules). Genetic mutations have been identified as the cause of inherited cancer risk in some RCC cancer–prone families; these mutations are estimated to account for only 1% to 2% of RCC cases overall.[3] It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC in conjunction with nongenetic risk factors. About 80% of sporadic RCC is of clear cell histopathology.[2] Non–renal cell cancers of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary.

RCC occurs in both sporadic and heritable forms. The following four major autosomal dominantly inherited RCC syndromes have been identified:

  • von Hippel-Lindau syndrome (VHL).
  • Hereditary leiomyomatosis and renal cell cancer (HLRCC).
  • Hereditary papillary renal cancer (HPRC).
  • Birt-Hogg-Dubé syndrome (BHD).

These genetic syndromes comprise the main focus of this summary. (Refer to the PDQ summary on Renal Cell Cancer Treatment for more information and the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information about sporadic kidney cancer.)

Natural History Varies by Histopathology

The natural history of each of the RCCs varies according to the characteristic histopathology of the renal tumors that arise in the specific syndrome. Although it is useful to follow the predominant reported natural history of each syndrome, each individual affected will need to be evaluated and monitored for occasional individual variations. The individual prognosis will depend upon the characteristics of the renal tumor at the time of detection and intervention and will differ for each syndrome (VHL, HPRC, BHD, and HLRCC). Prognostic determinants at diagnosis include the stage of the RCC, whether the tumor is confined to the kidney, primary tumor size, Fuhrman nuclear grade, and multifocality.[4-6]

Family History as a Risk Factor for RCC

Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease. The relative risk (RR) is estimated to be 2.5 for a sibling of an RCC-affected patient. This observation was reproducible in a number of studies.[7,8] Analysis of renal carcinomas up to the year 2000 in the Sweden Family-Cancer Database, which includes all Swedes born since 1931 and their biological parents, led to the observation that risk of RCC was particularly high in the siblings of those affected with RCC. The higher RR in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[7] Investigators in Iceland studied all patients in Iceland who developed RCC between 1955 and 1999 (1,078 cases). In addition, they used an extensive computerized database to perform a unique genealogic study that included more than 600,000 Icelandic individuals. The results revealed that nearly 60% of RCC patients in Iceland during this time period had either a first-degree relative or a second-degree relative with RCC.[8]

Because RCC accounts for only about 4% of all adult malignancies in the United States,[2,9] the presence of two or more family members with RCC may suggest a hereditary etiology. Having a relative affected with kidney cancer is one of the known epidemiologic risk factors for this disease. There is a 2.5 times greater chance of RCC arising in a sibling of an affected individual than in someone in the general population.[7,8,10] Young age at onset is also a clue to possible hereditary etiology. In contrast with sporadic RCC, which is generally diagnosed during the fifth to seventh decades of life, hereditary forms of kidney cancer are generally diagnosed at an earlier age. In a review from the National Cancer Institute of over 600 cases of hereditary kidney cancer, the median age at diagnosis was 37 years, with 70% of the cases being diagnosed at age 46 years or younger,[11] compared with a median age at diagnosis of 64 years in the overall population.[12]. Bilaterality and multifocality are common in most heritable RCC, except in HLRCC.

Other Risk Factors for RCC

Studies of environmental and lifestyle factors contributing to the risk of RCC focus almost exclusively on sporadic (i.e., nonhereditary) RCC. Smoking, hypertension, and obesity are the major environmental and lifestyle risk factors associated with RCC.[9] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably due to somatic mutations in the VHL gene.[13] Dietary intake of vegetables and fruits has been inversely associated with RCC. Greater intake of red meat and milk products have been associated with increased RCC risk, although not consistently.[14]


  1. American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed April 1, 2015.
  2. DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.
  3. Hung RJ, Moore L, Boffetta P, et al.: Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe. Cancer Epidemiol Biomarkers Prev 16 (6): 1287-90, 2007. [PUBMED Abstract]
  4. Vira MA, Novakovic KR, Pinto PA, et al.: Genetic basis of kidney cancer: a model for developing molecular-targeted therapies. BJU Int 99 (5 Pt B): 1223-9, 2007. [PUBMED Abstract]
  5. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
  6. Zbar B, Glenn G, Merino M, et al.: Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. J Urol 177 (2): 461-5; discussion 465, 2007. [PUBMED Abstract]
  7. Hemminki K, Li X: Familial risks of cancer as a guide to gene identification and mode of inheritance. Int J Cancer 110 (2): 291-4, 2004. [PUBMED Abstract]
  8. Gudbjartsson T, Jónasdóttir TJ, Thoroddsen A, et al.: A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas. Int J Cancer 100 (4): 476-9, 2002. [PUBMED Abstract]
  9. McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000. [PUBMED Abstract]
  10. Teh BT, Giraud S, Sari NF, et al.: Familial non-VHL non-papillary clear-cell renal cancer. Lancet 349 (9055): 848-9, 1997. [PUBMED Abstract]
  11. 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 32 (5): 431-7, 2014. [PUBMED Abstract]
  12. National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute, 2014. Available online. Last accessed December 5, 2014.
  13. Brauch H, Weirich G, Hornauer MA, et al.: Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J Natl Cancer Inst 91 (10): 854-61, 1999. [PUBMED Abstract]
  14. Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct. [PUBMED Abstract]
  • Updated: January 29, 2015