Genetics of Renal Cell Carcinoma (PDQ®): Genetics - Health Professional Information [NCI]

Inheritance and Risk of Renal Cell Carcinoma

Renal cell carcinoma (RCC) is commonly diagnosed in both men and women. In the United States in 2024, about 81,610 new cases of kidney cancer and renal pelvis cancer will occur, along with an estimated 14,390 deaths.[1] These cancers account for about 4.1% of all adult malignancies.[1] The male-to-female ratio is 1.9:1.[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). This summary does not address non-RCCs of the kidney, including cancer of the renal pelvis or renal medulla. Genetic pathogenic variants have been identified as the cause of inherited cancer risk in some RCC-prone families; these pathogenic variants are estimated to account for only 5% to 8% of RCC cases overall.[3,4] It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC along with nongenetic risk factors.

Studies of several sequencing cohorts have evaluated patients with RCC using genetic testing panels that included many genes not previously associated with hereditary RCC. Many of these cohorts reinforce that the rate of germline alterations in classic RCC genes aligns with prior estimates. These cohorts also show a high incidence of other pathogenic variants, some of which occurred in DNA repair genes. The rate of other pathogenic alterations ranged from 12.8% to 17.0%.[5,6,7,8,9] The incidence of other pathogenic alterations is higher than would be expected in the population. However, these cohorts are not population-based, and they are significantly enriched for cancer patients who have been recommended for germline testing.

A retrospective single-center study of patients with early-onset RCC (diagnosed before age 46 y), found that participants with clinical phenotypes suggestive of RCC-associated pathogenic variants—like bilateral or multifocal tumors, non–clear cell renal histology, and extra-renal primary cancers—had the highest yields on germline RCC panel testing.[10] There were 129 patients with clear cell RCC. A subset analysis of patients with unifocal, clear cell RCC did not reveal pathogenic variants on RCC genetic testing panels. Other studies have confirmed that individuals with bilateral or multifocal tumors were more likely to have a pathogenic variant in an RCC- or cancer-related gene.[11] However, 5% to 10% of individuals in these series had pathogenic variants in non-RCC–associated genes—primarily in DNA repair genes.[10,11] At this time, it is unclear if there is a causal relationship between RCC and these pathogenic alterations; the relationship requires additional study. It is plausible that these pathogenic variants increase RCC risk. However, RCC risk could also be elevated by other factors like an enriched population of high-risk individuals or overdetection of RCC from frequent scans in high-risk patients.

In contrast, several studies reported that the incidence of germline pathogenic variants is much lower (4.1% to 6.4%) in unselected individuals with RCC who underwent sequencing during a research study.[12,13] Most variants identified in these series were in genes classically associated with RCC. This finding suggests that the population studied may greatly influence the detection rate of pathogenic variants in cancer predisposition genes that are not typically associated with RCC.

RCC occurs in both sporadic and heritable forms. Four major RCC syndromes with autosomal dominant inheritance have been identified. PDQ summaries are available for each of these syndromes:

• Von Hippel-Lindau Disease (VHL).
• Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC).
• Hereditary Papillary Renal Carcinoma (HPRC).
• Birt-Hogg-Dubé Syndrome (BHD).

For more information about sporadic kidney cancer, see Renal Cell Cancer Treatment and Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment.

Natural History of Renal Cell Carcinoma

The natural history of each RCC syndrome is distinct and influenced by several factors, including histological features and underlying genetic alterations. Although it is useful to follow the predominant reported natural history of each syndrome, each affected individual must be evaluated and monitored for occasional individual variations. The individual prognosis depends on the characteristics of the renal tumor at the time of detection and intervention, which differs for each syndrome (VHL, HLRCC, HPRC, and BHD). 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.[14,15,16]

Family History as a Risk Factor for Renal Cell Carcinoma

Kidney cancer and renal pelvis cancer account for about 4.1% of all adult malignancies in the United States.[1] Epidemiological studies of RCC suggest that a family history of RCC is a risk factor for the disease.[4,17,18] An analysis of individuals with RCCs diagnosed before the year 2000 in the Sweden Family-Cancer Database included all Swedes born since 1931 and their biological parents. The study observed that the risk of RCC was particularly high in the siblings of those with RCC. Siblings of individuals with RCC had a higher relative risk (RR) than parent-child pairs.[17] Further work from this database confirms that 3% of individuals with RCC had a first-degree relative (FDR) with RCC.[19] Risk may be higher in individuals who have multiple FDRs with RCC and in women. Another study examined all patients in Iceland who developed RCC between 1955 and 1999 (1,078 cases). Investigators used an extensive computerized database to perform a unique genealogical study that included more than 600,000 Icelandic individuals. Results revealed that nearly 60% of Icelandic patients with RCC had a FDR or a second-degree relative (SDR) with RCC. Siblings of patients with RCC had an estimated RR of 2.5.[4] In a Korean study, individuals who had FDRs with RCC had a 2.29-fold increased risk of RCC. Risk did not appear to differ whether the FDR was a mother, father, or a sibling.[20] Modifying factors like obesity and hyperglycemia may further increase RCC risk in this high-risk population. Another study evaluated 80,309 monozygotic twins and 123,382 same-sex dizygotic twins in Denmark, Finland, Norway, and Sweden.[18] This study found excess cancer risk in twins whose co-twin was diagnosed with cancer. The estimated cumulative risks were an absolute 5% higher (95% confidence interval [CI], 4%–6%) in dizygotic twins (37%; 95% CI, 36%–38%) and an absolute 14% higher (95% CI, 12%–16%) in monozygotic twins (46%; 95% CI, 44%–48%)—for those whose co-twin also developed cancer—than in the overall cohort (32%). Overall heritability of cancer, calculated by assessing the relative contribution of heredity versus shared environment, was estimated to be 33%. Kidney cancer heritability was estimated to be 38% (95% CI, 21%–55%). Shared environmental factors did not significantly contribute to overall risk.

Young age at RCC onset is also a clue that hereditary etiology is possible. Unlike sporadic RCC, which is generally diagnosed during the fifth to seventh decades of life, hereditary forms of RCC are generally diagnosed at an earlier age. In a review of more than 600 cases of hereditary RCC from the National Cancer Institute, the median age of RCC diagnosis was 37 years, with 70% of cases being diagnosed at age 46 years or younger.[3] This age is lower than the median age of RCC diagnosis in the general population, which is 64 years.[21] Heritable RCCs are often multifocal and bilateral. A retrospective analysis of 1,235 patients with RCC who underwent genetic testing revealed that 6.1% of this population had positive genetic test results, 75.5% had negative test results, and 18.4% had a variant of unknown significance. Young age at RCC diagnosis was the only variable associated with a positive test result.[8] Other series showed that patients with non-clear cell advanced RCC may have an enrichment for pathogenic variants when compared with patients who had clear cell RCC; however, current research data are limited.[5,22]

While there is much debate about the referral criteria for hereditary RCC genetic testing, the following organizations have offered some guidance:

• VHL Alliance.
• Kidney Cancer Research Network of Canada.[23]
• National Comprehensive Cancer Network.[24]

These guidelines acknowledge that the following criteria can prompt a referral to genetic counseling: early age of RCC onset, family history of RCC (≥1 FDR/SDR with RCC), bilateral or multifocal RCCs, and suspicious RCC histology. A consensus statement published by a group of kidney cancer experts provides additional guidance that may help providers identify patients who can be referred to genetic counseling.[25]

When evaluating patients at risk of hereditary kidney cancer, specific clinical features help determine which test is the most appropriate to order. Single gene tests are available during family variant testing or when there is only suspicion for one specific kidney cancer syndrome. The following panel tests are also available: 1) broad cancer genetic panels of up to 100 genes associated with cancer predisposition, and 2) renal cancer genetic panels with 15 to 20 genes that have strong associations with hereditary kidney cancer syndromes. Most of these panels conduct targeted sequencing of the exon with little coverage of the intron, except for splice-site variants. In the future, RNA testing may be useful to evaluate variants of unknown significance identified by DNA testing, to add additional support for pathogenicity. Whole genome sequencing (WGS) can be considered for rare cases with clinical suspicion that had negative panel testing. WGS may detect structural variants in introns that can contribute to cancer predisposition. In a series of over 1,300 unselected patients with RCC who underwent WGS, 6.9% of patients had germline pathogenic variants identified in cancer predisposition genes.[12]

Other Risk Factors for Renal Cell Carcinoma

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.[26] In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably resulting from somatic variants in the VHL gene.[27] 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.[28]

References:

1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed June 21, 2024.
2. DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019.
3. 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.
4. 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.
5. Carlo MI, Mukherjee S, Mandelker D, et al.: Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma. JAMA Oncol 4 (9): 1228-1235, 2018.
6. Hartman TR, Demidova EV, Lesh RW, et al.: Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer. Sci Rep 10 (1): 13518, 2020.
7. Abou Alaiwi S, Nassar AH, Adib E, et al.: Trans-ethnic variation in germline variants of patients with renal cell carcinoma. Cell Rep 34 (13): 108926, 2021.
8. Nguyen KA, Syed JS, Espenschied CR, et al.: Advances in the diagnosis of hereditary kidney cancer: Initial results of a multigene panel test. Cancer 123 (22): 4363-4371, 2017.
9. Smith PS, West H, Whitworth J, et al.: Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity. Genes Chromosomes Cancer 60 (1): 5-16, 2021.
10. Truong H, Sheikh R, Kotecha R, et al.: Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing. Eur Urol Oncol 4 (6): 993-1000, 2021.
11. Nguyen CB, Knaus C, Li J, et al.: Pathogenic Germline Mutational Landscape in Patients With Renal Cell Carcinoma and Associated Clinicopathologic Features. JCO Precis Oncol 7: e2300168, 2023.
12. Yngvadottir B, Andreou A, Bassaganyas L, et al.: Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases. Hum Mol Genet 31 (17): 3001-3011, 2022.
13. Sekine Y, Iwasaki Y, Aoi T, et al.: Different risk genes contribute to clear cell and non-clear cell renal cell carcinoma in 1532 Japanese patients and 5996 controls. Hum Mol Genet 31 (12): 1962-1969, 2022.
14. 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.
15. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003.
16. 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.
17. 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.
18. Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016.
19. Jakobsson RG, Nasic S, Bratt O, et al.: Family History and Risk of Renal Cell Carcinoma: A National Multiregister Case-Control Study. J Urol 211 (1): 71-79, 2024.
20. Lee SW, Kim HJ, Kazmi SZ, et al.: Familial Risk of Renal Cell Cancer and Interaction with Obesity and Hyperglycemia: A Population-Based Study. J Urol 208 (2): 251-258, 2022.
21. National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed September 18, 2024.
22. Santos M, Lanillos J, Roldan-Romero JM, et al.: Prevalence of pathogenic germline variants in patients with metastatic renal cell carcinoma. Genet Med 23 (4): 698-704, 2021.
23. Reaume MN, Graham GE, Tomiak E, et al.: Canadian guideline on genetic screening for hereditary renal cell cancers. Can Urol Assoc J 7 (9-10): 319-23, 2013 Sep-Oct.
24. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 3.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2022. Available online with free registration. Last accessed September 30, 2024.
25. Bratslavsky G, Mendhiratta N, Daneshvar M, et al.: Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement. Cancer 127 (21): 3957-3966, 2021.
26. McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000.
27. 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.
28. Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct.

Major Heritable Renal Cell Carcinoma Syndromes

There are four major hereditary renal cell carcinoma (RCC) syndromes. These syndromes are summarized in detail in the following PDQ summaries and in Table 1 below:

• Von Hippel-Lindau Disease (VHL).
• Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC).
• Hereditary Papillary Renal Carcinoma (HPRC).
• Birt-Hogg-Dubé Syndrome (BHD).

Table 1. Hereditary Renal Cell Cancer (RCC) Syndromes and Susceptibility Genes

Syndrome (Inheritance Pattern)	Gene Locus, Gene Type (Protein)	Renal Tumor Pathology	Cumulative Cancer Risk	Nonrenal Tumors and Associated Abnormalities
AD = autosomal dominant; ccRCC = clear cell renal cell carcinoma; CNS = central nervous system; PHEO = pheochromocytoma.
Von Hippel-Lindau disease(VHL) (AD)[1,2]	VHL3p26,tumor suppressor(pVHL)	ccRCC (multifocal)	24%–45%	CNS hemangioblastoma, retinal hemangioblastomas, PHEO, pancreatic neuroendocrine tumor, endolymphatic sac tumor, cystadenoma of the pancreas, the epididymis, and the broad ligament
Hereditary leiomyomatosis and renal cell cancer(HLRCC) (AD)[3,4,5,6]	FH1q42.1, tumor suppressor (fumarate hydratase)	HLRCC-associated RCC	Up to 32%	Cutaneous leiomyomas, uterine leiomyomas (fibroids)
Hereditary papillary renal carcinoma (HPRC) (AD)[7,8]	MET7q34, proto-oncogene (hepatocyte growth factor receptor)	Papillary RCC (formerly known as type 1 papillary RCC)	Approaching 100%	None known
Birt-Hogg-Dubé syndrome(BHD) (AD)[9,10,11,12]	FLCN17p11.2, tumor suppressor (folliculin)	Hybrid oncocytic, chromophobe, oncocytoma, papillary, clear cell	15%–30%	Cutaneous: fibrofolliculomas/ trichodiscomas
				Pulmonary: lung cysts, spontaneous pneumothoraces

These major RCC syndromes are transmitted via an autosomal dominant mode of inheritance. This means that the altered gene is present in one of the parents and that the chances of transmitting this gene and the disease to the offspring is 50% for each pregnancy. Genetic tests performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories are available for the genes associated with VHL, HLRCC, HPRC, and BHD. Genetic counseling is a prerequisite for genetic testing. For more information, see Cancer Genetics Risk Assessment and Counseling.

References:

1. Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194 (3): 629-42, 1995.
2. Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003.
3. Launonen V, Vierimaa O, Kiuru M, et al.: Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 98 (6): 3387-92, 2001.
4. Alam NA, Olpin S, Leigh IM: Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol 153 (1): 11-7, 2005.
5. 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 73 (1): 95-106, 2003.
6. 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 43 (1): 18-27, 2006.
7. 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 16 (1): 68-73, 1997.
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 172 (4 Pt 1): 1256-61, 2004.
9. Toro JR, Wei MH, Glenn GM, et al.: 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 45 (6): 321-31, 2008.
10. Toro JR, Glenn G, Duray P, et al.: Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 135 (10): 1195-202, 1999.
11. Zbar B, Alvord WG, Glenn G, et al.: Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 11 (4): 393-400, 2002.
12. Pavlovich CP, Walther MM, Eyler RA, et al.: Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 26 (12): 1542-52, 2002.

Latest Updates to This Summary (10 / 15 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Inheritance and Risk of Renal Cell Carcinoma (RCC)

Added text to state that other studies have confirmed that individuals with bilateral or multifocal tumors were more likely to have a pathogenic variant in a renal cell carcinoma (RCC)- or cancer-related gene (cited Nguyen et al. as reference 11). Revised text to state that 5% to 10% of individuals in these series had pathogenic variants in non-RCC associated genes.

Added text to state that further work from this database confirms that 3% of individuals with RCC had a first-degree relative (FDR) with RCC (cited Jakobsson et al. as reference 19). Risk may be higher in individuals who have multiple FDRs with RCC and in women. Also added text to state that in a Korean study, individuals who had FDRs with RCC had a 2.29-fold increased risk of RCC. Risk did not appear to differ whether the FDR was a mother, father, or a sibling (cited Lee et al. as reference 20). Modifying factors like obesity and hyperglycemia may further increase RCC risk in this high-risk population.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of renal cell carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Renal Cell Carcinoma are:

• Alexandra Perez Lebensohn, MS, CGC (National Cancer Institute)
• Brian Matthew Shuch, MD (UCLA Health)
• Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)

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PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Renal Cell Carcinoma. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/renal-cell-carcinoma-genetics. Accessed <MM/DD/YYYY>. [PMID: 26389510]

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Last Revised: 2024-10-15