Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version
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 RiskRenal 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 SyndromesThe 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 ManagementRegular 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
[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. 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.]
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 Alliance.
- 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 variants 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
- American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed January 23, 2019.
- DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.
- 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]
- 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]
- 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]
- Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
- 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]
- Siegel RL, Miller KD, Jemal A: Cancer statistics, 2016. CA Cancer J Clin 66 (1): 7-30, 2016 Jan-Feb. [PUBMED Abstract]
- 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]
- 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]
- National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 14, 2018.
- 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]
- 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]
- 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]
- McLaughlin JK, Lipworth L: Epidemiologic aspects of renal cell cancer. Semin Oncol 27 (2): 115-23, 2000. [PUBMED Abstract]
- 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]
- Chow WH, Devesa SS: Contemporary epidemiology of renal cell cancer. Cancer J 14 (5): 288-301, 2008 Sep-Oct. [PUBMED Abstract]
Major Heritable Renal Cell Cancer Syndromes
Four major heritable renal cell cancer (RCC) syndromes (von Hippel-Lindau disease [VHL], hereditary leiomyomatosis and renal cell cancer [HLRCC], Birt-Hogg-Dubé syndrome [BHD], and hereditary papillary renal carcinoma [HPRC]) with autosomal dominant inheritance are listed in Table 1, along with their susceptibility genes. These syndromes are summarized in detail in the following sections of this summary.
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, BHD, HLRCC, and HPRC. Genetic counseling is a prerequisite for genetic testing. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
References
- Choyke PL, Glenn GM, Walther MM, et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194 (3): 629-42, 1995. [PUBMED Abstract]
- Lonser RR, Glenn GM, Walther M, et al.: von Hippel-Lindau disease. Lancet 361 (9374): 2059-67, 2003. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
Von Hippel-Lindau Disease
Introduction
Von Hippel-Lindau disease (VHL) (OMIM) is an autosomal dominant disease with a predisposition to multiple neoplasms. Germline pathogenic variants in the VHL genepredispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system (CNS) hemangioblastomas; retinal hemangioblastomas; clear cell renal cell cancers (ccRCCs) and renal cysts; pheochromocytomas, cysts, cystadenomas, and neuroendocrine tumors (NETs) of the pancreas; endolymphatic sac tumors (ELSTs); and cystadenomas of the epididymis (males) and of the broad ligament (females).[1-4] A multidisciplinary approach is required for the evaluation, and in some cases the management, of individuals with VHL. Specialists involved in the care of individuals with VHL may include urologic oncology surgeons, neurosurgeons, general surgeons, ophthalmologists, endocrinologists, neurologists, medical oncologists, genetic counselors, and medical geneticists.
Genetics
VHL gene
The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 at cytoband 3p25-26.[5] VHL pathogenic variants occur in all three exons of this gene. Most affected individuals inherit a germline pathogenic variant of VHL from an affected parent and a normal (wild-type) VHL copy from their unaffected parent. VHL-associated tumors conform to Knudson’s “two-hit” hypothesis,[6,7] in which the clonal origin or first transformed cell of the tumor occurs only after both VHL alleles in a cell are inactivated. The inherited germline pathogenic variant in VHL represents the first "hit", which is present in every cell in the body. The second “hit” is a somatic pathogenic variant, one that occurs in a specific tissue at some point after a person's birth. It damages the normal, or wild-type, VHL allele, creating a clonal neoplastic cell of origin, which may proliferate into a tumor mass.
Prevalence and rare founder effects
The incidence of VHL is estimated to be between 1 per 27,000 and 1 per 43,000 live births in the general population.[8-10] The prevalence is estimated to be between 1 in 31,000 to 1 in 91,000 individuals.[9-12] Precise quantification of this number is a challenge because it requires comprehensive screening of potentially at-risk blood relatives of individuals diagnosed with VHL. Within this population, the large number of unique pathogenic variants in this small three-exon gene indicates that most family clusters have not arisen from a single founder.
Penetrance of pathogenic variants
Risk factors for VHL
Each offspring of an individual with VHL has a 50% chance of inheriting the VHL pathogenic variant allele from their affected parent. (Refer to the Genetic diagnosis section of this summary for more information.)
Genotype-phenotype correlations
Specific pathogenic variant types leading to VHL clinical manifestations include missense, nonsense, frameshifts, insertions, partial and complete deletions, and splice-site variantsof VHL. The specific alteration may influence clinical manifestations. Two major clinical phenotypes of VHL have been described. Type I, commonly associated with large gene deletions, is characterized by the development of all VHL-associated lesions except pheochromocytoma. Type II, more commonly associated with missense variants, is characterized by the development of all clinical manifestations including pheochromocytoma. Type II clinical phenotype is subdivided into Type IIA (low risk of RCC), Type IIB (high risk of renal cell cancer [RCC]), and Type IIC (no RCC development, where the predominant clinical picture is characterized by CNS hemangioblastoma and pheochromocytoma development). Overall, the risk of RCC correlates with the loss of hypoxia-inducible factor (HIF)2-alpha regulation by the specific VHL germline variant.[13-16] Specific alterations can be useful in segregating risks; however, significant overlap exists, and surveillance tailored according to phenotype is not generally advised.
De novo pathogenic variants and mosaicism
When a VHL diagnosis is made in an individual whose ancestors (biological parents and their kindred) do not have VHL, this may result from a de novo (new) VHL pathogenic variant in the affected individual. Patients diagnosed with VHL, who have no family historyof VHL, have been estimated to comprise about 23% of VHL kindreds.[17] A new variant is by definition a postzygotic event, because it is not transmitted from a parent.
Depending on the embryogenesis stage at which the new variant occurs, there may be different somatic cell lineages carrying the variant; this influences the extent of mosaicism. Mosaicism is the presence in an individual of two or more cell lines that differ in genotypebut which arise from a single zygote.[18] If the postzygotic de novo variant affects the gonadal cell line, there is a risk of transmitting a germline variant to offspring.[17]
Allelic disorder
VHL-associated polycythemia (also known as familial erythrocytosis type 2 or Chuvash polycythemia) is a rare, autosomal recessive blood disorder caused by homozygous or compound heterozygous pathogenic variants in VHL in which affected individuals develop abnormally high numbers of red blood cells (polycythemia). The affected individuals have biallelic pathogenic variants in the VHL gene. It had been originally thought that the typical VHL syndromic tumors do not occur in these affected individuals.[19-21]
Other genetic alterations
In sporadic RCC, mutational inactivation of the VHL gene is the most frequent molecular event. In addition to VHL inactivation, sporadic ccRCC tumors harbor frequent variants in other genes, including PBRM1, SETD2, and BAP1.[22,23] Mutational inactivation of PBRM1, SETD2, and BAP1 are “second hit” events occurring after VHL alterations in sporadic ccRCC, and they contribute to development and growth of ccRCC.[24,23] Germline pathogenic variants in PBRM1 and BAP1 result in the development of hereditary forms of ccRCC.[25] The role of PBRM1, BAP1, and SETD2 in VHL-related ccRCC growth and progression is under investigation.
Molecular Biology
The VHL tumor suppressor gene encodes two proteins: a 213 amino acid protein (pVHL30) and a 154 amino acid protein, which is the product of internal translation.[26] The best-studied function of pVHL, linked to its ability to suppress tumor formation, is the regulation of HIF activity. Other reported functions of pVHL include regulation of extracellular matrix formation, microtubule and centrosome maturation, and inactivation of p53.[27-30] These functions are described in more detail in the following paragraphs.
HIF1-alpha and HIF2-alpha
pVHL regulates protein levels of HIF1-alpha and HIF2-alpha in the cell by acting as a substrate recognition site for HIF as part of an E3 ubiquitin ligase complex.[30] In normoxic conditions, HIF1-alpha and HIF2-alpha are enzymatically hydroxylated by intracellular prolyl hydroxylases. The hydroxylated HIF subunits are bound by the VHL protein complex, covalently linked to ubiquitin, and degraded by the S26 proteasome.[31,32]
Hypoxia inactivates prolyl hydroxylases, leading to lack of HIF hydroxylation. Nonhydroxylated HIF1-alpha and HIF2-alpha are not bound to the VHL protein complex for ubiquitination, and, therefore, accumulate. The resulting constitutively high levels of HIF1-alpha and HIF2-alpha drive increased transcription of a variety of genes, including growth and angiogenic factors, enzymes of the intermediary metabolism, and genes promoting stemness-like cellular phenotypes.[33]
HIF1-alpha and HIF2-alpha possess distinct and partially contrasting functional characteristics. In the context of RCC, it appears that HIF2-alpha acts as an oncogene, and HIF1-alpha acts as a tumor suppressor gene. HIF2-alpha may preferentially upregulate Myc activity, whereas HIF1-alpha may inhibit Myc activity.[34] Hypoxia-associated factor has been shown to increase HIF2-alpha transactivation [35] and HIF1-alpha instability.[36] Preferential loss of chromosome 14q, the locus for the HIF1-alpha gene, results in decreased levels of HIF1-alpha protein.[37]
Numerous studies using xenografted or transgenic animal models have shown that inactivation of HIF2-alpha by pVHL is necessary and sufficient for tumor suppression by the pVHL proteins. HIF2-alpha is now an established therapeutic target for VHL-related malignancies.[38-40] Specific HIF2-alpha inhibitors are in preclinical and clinical testing.[41-43]
Microtubule regulation and cilia centrosome control
Emerging data point to the importance of pVHL-mediated control of the primary cilium and the cilia centrosome cycle. The nonmotile primary cilium acts as a mechanosensor, is a regulator of cell signaling, and controls cellular entry into mitosis.[44] Loss of primary ciliary function results in the loss of the cell’s ability to maintain planar cell polarity, which results in cyst formation.[45] Loss of pVHL results in loss of the primary cilium.[46] pVHL binds to and stabilizes microtubules [47] in a glycogen synthase 3–dependent fashion.[48] Loss of pVHL or expression of variant pVHL in cells also results in unstable astral microtubules, dysregulation of the spindle assembly checkpoint, and an increase in aneuploidy.[29]
Cell cycle control
pVHL reintroduction induces cell cycle arrest and p27 upregulation after serum withdrawal in VHL null cell lines.[27] Additionally, pVHL destabilizes Skp2, and upregulates p27 in response to DNA damage.[49] Nuclear localization and intensity of p27 is inversely associated with tumor grade.[50] pVHL binds to [51] and facilitates phosphorylation of p53 in an ATM-dependent fashion.[52]
Extracellular matrix control
Regulation of oncogenic autophagy
In ccRCC, oncogenic autophagy dependent on microtubule-associated protein 1 light chain 3 alpha and beta (LC3A and LC3B) is stimulated by activity of the transient receptor potential melastatin 3 (TRPM3) channel through multiple complementary mechanisms. The VHL tumor suppressor represses this oncogenic autophagy in a coordinated manner through the activity of miR-204, which is expressed from intron 6 of the gene encoding TRPM3. TRPM3 represents an actionable target for ccRCC treatment.[55,56]
Animal models of VHL
VHL knockout mice die in utero. Heterozygous VHL mice develop vascular liver lesions reminiscent of hemangioblastomas.[57] Conditional targeted inactivation of the Vhlh gene in the mouse kidney results in the generation of VHL-resembling cysts but not RCC. Coordinate inactivation of Vhlh and Pten results in a higher rate of cyst formation, but no obvious RCC.[58] Murine homologues of the VHL R200W pathogenic variant induced polycythemia in mice, phenocopying Chuvash polycythemia.[59] The discovery of several new potential tumor suppressor genes inactivated in the context of RCC, including PBRM1,[60] SETD2,[61] and BAP1 [62] provide new avenues for developing relevant animal models of at least some VHL manifestations.
Clinical Manifestations
Age ranges and cumulative risk of different syndrome-related neoplasms
The age at onset of VHL varies both from family to family and between members of the same family. This fact informs the guidelines for starting age and frequency of presymptomatic surveillance examinations. The youngest age at onset of specific VHL components is observed for retinal hemangioblastomas and pheochromocytomas; targeted screening is recommended in children younger than 10 years. At least one study has demonstrated that the incidence of new lesions varies depending on patient age, the underlying pathogenic variant, and the organ involved.[63] Examples of reported mean ages and age ranges of VHL clinical manifestations are summarized in Table 2.
(Refer to the Clinical diagnosis section of this summary for more information.)
VHL familial phenotypes
Four clinical types of VHL have been described. In 1991, researchers classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma).[11] In 1995, VHL type 2 was further subdivided into type 2A (with pheochromocytoma, but without RCC) and type 2B (with pheochromocytoma and RCC).[64] More recently, it was reported that VHL type 2C comprises patients with isolated pheochromocytoma without hemangioblastoma or RCC.[65] These specific VHL phenotypes are summarized in Table 3.
Tissue Manifestations
More than 55% of VHL-affected individuals develop only multiple renal cell cysts. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass.[66] Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2) and minimally invasive,[67] and their rate of growth varies widely.[68] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a simple cyst to a solid lesion was infrequent.[66] Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL. Figure 1 depicts bilateral renal tumors in a patient with VHL.
Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[68,69] RCCs often remain asymptomatic for long intervals.
Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[2] Pancreatic cysts and cystadenomas are not malignant, but pancreatic NETs possess malignant characteristics and are typically resected if they are 3 cm or larger (2 cm if located in the head of the pancreas).[70] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[71]
Retinal hemangioblastomas
Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients.[72] Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 25 years.[1,2] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children as young as 1 year.[2,73,74]
Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[72] The median number of lesions per affected eye is approximately six.[75] Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[76]
Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients [72] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[77] Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[75,78]
Cerebellar and spinal hemangioblastomas
Hemangioblastomas are the most common disease manifestation in patients with VHL, affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[79] The mean age at onset of CNS hemangioblastomas is 29.1 years (range, 7–73 y).[80] After a mean follow-up of 7 years, 72% of the 225 patients studied developed new lesions.[81] Fifty-one percent of existing hemangioblastomas remained stable. The remaining lesions exhibited heterogeneous growth rates, with cerebellar and brainstem lesions growing faster than those in the spinal cord or cauda equina. Approximately 12% of hemangioblastomas developed either peritumoral or intratumoral cysts, and 6.4% were symptomatic and required treatment. Increased tumor burden or total tumor number detected was associated with male sex, longer follow-up, and genotype (all P < .01). Partial germline deletions were associated with more tumors per patient than were missense variants (P < .01). Younger patients developed more tumors per year. Hemangioblastoma growth rate was higher in men than in women (P < .01). Figures 2 and 3 depict cerebellar and spinal hemangioblastomas, respectively, in patients with VHL.
Pheochromocytomas and paragangliomas
The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%.[82,83] Of patients with VHL-associated pheochromocytomas, 44% developed disease in both adrenal glands.[84] The rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL,[85] and approximately two-thirds will experience physical manifestations such as hypertension, tachycardia, and palpitations.[82] Patients with a partial loss of VHL function (Type 2 disease) are at higher risk of pheochromocytoma than are VHL patients with a complete loss of VHL function (Type 1 disease); the latter develop pheochromocytoma very rarely.[13,14,82,86] The rate of VHL germline pathogenic variants in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL.[87]
Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[88] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[84]
The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years,[83,89] and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions in one series (19 vs. 34 y; P < .001).[89] Diagnosis of pheochromocytoma was made in patients as young as 5 years in one cohort,[83] providing a rationale for early testing. All 21 pediatric patients with pheochromocytomas in this 273-patient cohort had elevated plasma normetanephrines.[83]
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