Renal cell carcinoma (RCC) is commonly diagnosed in both men and women. In the United States in 2022, about 79,000 new cases of kidney cancer and renal pelvis cancer will occur and lead to an estimated 13,920 deaths. This cancer accounts for about 4.1% 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.
Several sequencing cohorts have evaluated patients with RCC using genetic testing panels that included many genes that have not previously been 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 alterations, some of which occurred in DNA repair genes; the rate of other pathogenic alterations ranged from 12.8% to 17.0%.[5-9] 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. 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 an overdetection of RCC from frequent scans in high-risk patients.
For more information on sporadic kidney cancer, see Renal Cell Cancer Treatment and Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment.
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 must be evaluated and monitored for occasional individual variations. The individual prognosis will depend on 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.[10-12]
RCC accounts for about 4.1% of all adult malignancies in the United States. Epidemiological studies of RCC suggest that a family history of RCC is a risk factor for the disease.[4,13,14] An analysis of 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 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. This suggests that a recessive gene contributes to the development of sporadic RCC. In another study, 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 genealogical study that included more than 600,000 Icelandic individuals. Results revealed that nearly 60% of Icelandic patients with RCC had a first-degree relative (FDR) or a second-degree relative (SDR) with RCC. Siblings of patients with RCC had an estimated RR of 2.5. A study that evaluated 80,309 monozygotic twins and 123,382 same-sex dizygotic twins in Denmark, Finland, Norway, and Sweden 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 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%. 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. In contrast with 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 over 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. This is lower than the median age of RCC diagnosis in the general population, which is 64 years. 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. 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.[5,16]
While there is much debate about the referral criteria for hereditary RCC genetic testing, the following organizations have offered some guidance:
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.
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.
There are four major heritable renal cell carcinoma (RCC) syndromes. These syndromes are summarized in detail in the following PDQ summaries and in Table 1 below:
|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]||VHL 3p26, 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) [3-6]||FH 1q42.1, tumor suppressor (fumarate hydratase)||HLRCC-associated RCC||Up to 32%||Cutaneous leiomyomas, uterine leiomyomas (fibroids)|
|Hereditary papillary renal carcinoma (HPRC) (AD) [7,8]||MET 7q34, proto-oncogene (hepatocyte growth factor receptor)||Papillary type 1||Approaching 100%||None known|
|Birt-Hogg-Dubé syndrome (BHD) (AD) [9-12]||FLCN 17p11.2, tumor suppressor (folliculin)||Hybrid oncocytic, chromophobe, oncocytoma, papillary, clear cell||15%–30%||Cutaneous: fibrofolliculomas/ trichodiscomas|
|Pulmonary: lung cysts, spontaneous pneumothoraces|
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. For more information, see Cancer Genetics Risk Assessment and Counseling.
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.
Added text to state that while there is much debate about the referral criteria for hereditary renal cell carcinoma (RCC) genetic testing, the following organizations have offered some guidance. Also added National Comprehensive Cancer Network as reference 19.
Added text to state that guidelines acknowledge that the following criteria can prompt a referral to genetic counseling: early age of RCC onset, family history of 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 (cited Bratslavsky et al. as reference 20).
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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.
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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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