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Home > Patient & Family Resources > Health Library > Genetics of Renal Cell Carcinoma (PDQ®): Genetics - Health Professional Information [NCI]
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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Renal cell carcinoma (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2021, about 76,080 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to an estimated 13,780 deaths. This cancer accounts for about 4% of all adult malignancies. The male-to-female ratio is 1.9:1. 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). Non-RCCs of the kidney, including cancer of the renal pelvis or renal medulla, are not addressed in this summary. 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 in conjunction with nongenetic risk factors.
RCC occurs in both sporadic and heritable forms. The following four major autosomal dominantly inherited RCC syndromes have been identified. PDQ summaries are available for each of these syndromes:
(Refer to the PDQ summaries on Renal Cell Cancer Treatment and Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information about sporadic kidney cancer.)
Natural History of Renal Cell Carcinoma
The natural history of each RCC syndrome is distinct and influenced by several factors, including histologic features and underlying genetic alterations. Although it is useful to follow the predominant reported natural history of each syndrome, each affected individual 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, 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.[5,6,7]
Family History as a Risk Factor for Renal Cell Carcinoma
RCC accounts for about 4% of all adult malignancies in the United States. Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease.[4,9,10] An analysis of renal carcinomas 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 risk of RCC was particularly high in the siblings of those affected with RCC. The higher relative risk (RR) in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma. Investigators 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 had either a first-degree relative or a second-degree relative with RCC, with an estimated RR of 2.5 for a sibling of an RCC-affected patient. A study that evaluated 80,309 monozygotic twin individuals and 123,382 same-sex dizygotic twin individuals in Denmark, Finland, Norway, and Sweden found an 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 twins whose co-twin also developed cancer—than that 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%. Heritability of kidney cancer was estimated to be 38% (95% CI, 21%–55%), with shared environmental factors not showing a significant contribution to overall risk.
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, compared with a median age at diagnosis of 64 years in the overall population. Bilaterality and multifocality are common in most heritable RCCs. 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. The only variable associated with a positive test result was younger age at diagnosis of RCC.
There is no consensus regarding whom to refer for genetic consultation for a possible hereditary kidney cancer syndrome, although the following organizations have offered guidance:
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. In addition, workers who were reportedly exposed to the environmental carcinogen trichloroethylene developed sporadic clear cell RCC, presumably resulting from somatic mutations in the VHL gene. 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.
Four major heritable renal cell carcinoma (RCC) syndromes (von Hippel-Lindau disease [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], hereditary papillary renal carcinoma [HPRC], and Birt-Hogg-Dubé syndrome [BHD]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following PDQ summaries:
Autosomal dominant mode of inheritance is the pattern of transmission reported within the families affected by these major RCC syndromes. Autosomal dominant means that it is sufficient for the altered gene to be 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. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
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.
This summary was extensively revised.
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® - NCI's Comprehensive Cancer Database pages.
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 who care for cancer 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).
Board members review recently published articles each month to determine whether an article should:
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:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
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]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2021-03-11
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