Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®) 1/6 –Health Professional Version - National Cancer Institute

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version - National Cancer Institute

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version

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ON THIS PAGE

• Executive Summary
• Introduction
• Major Heritable Renal Cell Cancer Syndromes
• Von Hippel-Lindau Disease
• Hereditary Leiomyomatosis and Renal Cell Cancer
• Birt-Hogg-Dubé Syndrome
• Hereditary Papillary Renal Carcinoma
• Changes to This Summary (11/01/2019)
• About This PDQ Summary

Executive Summary

This executive summary reviews the topics covered in this PDQ summary on the genetics of kidney cancer (renal cell cancer), with hyperlinks to detailed sections below that describe the evidence on each topic.

• Inheritance and Risk
  Renal cell cancer (RCC), which is distinct from kidney cancer that involves the renal pelvis or renal medulla, occurs in both sporadic and heritable forms. Autosomal dominantly inherited pathogenic germline 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. It is likely that other undiscovered genes and background genetic factors contribute to the development of familial RCC in conjunction with nongenetic risk factors.

• Associated Genes and Syndromes
  The following four major autosomal dominantly inherited RCC syndromes have been identified: von Hippel-Lindau disease (VHL, caused by pathogenic variants in VHL); hereditary leiomyomatosis and renal cell cancer (HLRCC, caused by pathogenic variants in FH); Birt-Hogg-Dubé syndrome (BHD, caused by pathogenic variants in FLCN); and hereditary papillary renal carcinoma (HPRC, caused by pathogenic variants in MET). Each of these syndromes, with the exception of HPRC, is associated with other benign or malignant tumors in other organs.

• Clinical Management
  Regular surveillance is a mainstay in individuals found to have or be at risk of carrying a pathogenic variant in VHL, FH, FLCN, or MET. Surveillance recommendations include regular screening for both renal and nonrenal manifestations of disease.
  VHL-associated renal tumors of 3 cm in size are commonly managed with surgery. Nephron-sparing techniques are typically employed as they have been shown to preserve renal function. Ablative techniques including radiofrequency ablation and cryoablation may be used in patients with smaller tumors who are at high operative risk. Chemotherapeutic agents such as sunitinib have been studied in the treatment of patients with VHL and found to be effective in treating VHL-associated RCC but not hemangioblastomas. Extrarenal manifestations of VHL, such as retinal hemangioblastomas, central nervous system lesions, pheochromocytomas, and pancreatic cysts and neuroendocrine tumors, often require subspecialty evaluation and may require surgical intervention.
  HLRCC-associated RCCs are biologically quite aggressive, so early and extensive surgical management (e.g., radical nephrectomy or partial nephrectomy with wide margins) may be necessary. Targeted therapies including the use of bevacizumab/erlotinib in a combination regimen and vandetanib are currently under investigation. HLRCC-associated cutaneous lesions generally need no intervention. If symptomatic, surgery, cryoablation, and/or laser therapy may be considered. A small randomized controlled trial has shown that botulinum toxin A may improve quality of life in HLRCC patients with painful skin lesions. Hormonal and/or pain management medications may be given to provide release from uterine leiomyoma-related pain. The leiomyomas may also be removed surgically.
  Both BHD-associated RCCs and HPRC-associated RCCs are typically managed with partial nephrectomy once they reach 3 cm. MET inhibition is being studied as a potential targeted therapy in individuals with HPRC-associated RCC. BHD-associated cutaneous lesions generally need no intervention. BHD patients are also at increased risk of spontaneous pneumothorax, which is managed as it would be in the general population.

Introduction

In This Section

• Natural History
• Family History as a Risk Factor for RCC
• Other Risk Factors for RCC

[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.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

[Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. Refer to OMIMExit Disclaimer for more information.]

Renal cell cancer (RCC) is among the more commonly diagnosed cancers in both men and women. In the United States in 2019, about 73,820 cases of kidney cancer and renal pelvis cancer are expected to occur and lead to an estimated 14,770 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). 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:

• von Hippel-Lindau disease (VHL).
• Hereditary leiomyomatosis and renal cell cancer (HLRCC).
• Hereditary papillary renal carcinoma (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 and the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information about sporadic kidney cancer.)

Natural History

The natural history of each 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 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.[5-7]

Family History as a Risk Factor for RCC

RCC accounts for about 4% of all adult malignancies in the United States.[8] Epidemiologic studies of RCC suggest that a family history of RCC is a risk factor for the disease.[4,9,10] 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 relative risk (RR) in siblings than in parent-child pairs suggests that a recessive gene contributes to the development of sporadic renal carcinoma.[9] 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 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.[4] 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.[10] 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,[3] compared with a median age at diagnosis of 64 years in the overall population.[11]. Bilaterality and multifocality are common in most heritable RCC. 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.[12]

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:

• American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.[13]
• VHL AllianceExit Disclaimer.
• Kidney Cancer Research Network of Canada.[14]

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.[15] 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.[16] 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.[17]

References

1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available onlineExit Disclaimer. Last accessed June 7, 2019.
2. DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.
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. [PUBMED Abstract]
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. [PUBMED Abstract]
5. 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]
6. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
7. 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]
8. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2016. CA Cancer J Clin 66 (1): 7-30, 2016 Jan-Feb. [PUBMED Abstract]
9. 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]
10. 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. [PUBMED Abstract]
11. National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute. Available online. Last accessed October 16, 2019.
12. 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. [PUBMED Abstract]
13. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
14. 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. [PUBMED Abstract]
15. McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000. [PUBMED Abstract]
16. 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]
17. Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct. [PUBMED Abstract]