Hereditary kidney cancer

Unique Opportunity for Disease-based Therapy


  • This article is US Government work and, as such, is in the public domain in the United States of America.

  • This educational proceedings publication is based on a symposium held on June 27-28, 2008, in Cambridge, Massachusetts.


Kidney cancer is not a single disease; it is comprised of several different types of cancer, each with a different histology, with a different clinical course, caused by a different gene, and responding differently to therapy. The VHL gene is the gene for the hereditary cancer syndrome, von Hippel-Lindau, as well as for the common form of sporadic, noninherited, clear cell kidney cancer. Understanding the VHL-hypoxia inducible factor (HIF) pathway has provided the foundation for the development of several agents targeting this pathway, such as sunitinib, sorafenib, and temsirolimus. Hereditary papillary renal carcinoma (HPRC) is a hereditary renal cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal, type 1 papillary renal cell carcinoma. The genetic defect underlying HPRC is MET, the cell surface receptor for hepatocyte growth factor. Mutations of MET also have been identified in a subset of tumors from patients with sporadic type 1 papillary renal cell carcinoma (RCC). Clinical trials targeting the MET pathway are currently underway in patients with HPRC and in patients with sporadic (nonhereditary) papillary kidney cancer. The BHD gene (also known as folliculin or FLCN) is the gene for Birt-Hogg-Dube syndrome, an autosomal-dominant genodermatosis associated with a hereditary form of chromophobe and oncocytic, hybrid RCC. Preclinical studies are underway targeting the BHD gene pathway in preparation for clinical trials in Birt-Hogg-Dube and sporadic chromophobe RCC. Patients with hereditary leiomyomatosis RCC (HLRCC) are at risk for developing cutaneous and uterine leiomyomas and a very aggressive type of RCC. HLRCC is characterized by germline mutation of the Krebs cycle enzyme, fumarate hydratase (FH). Studies of the tricarboxylic acid cycle and the VHL-HIF pathways have provided the foundation for therapeutic approaches in patients with HLRCC-associated kidney cancer as well as other hereditary and sporadic forms of RCC. Cancer 2009;115(10 suppl):2252-61. Published 2009 by the American Cancer Society.

Kidney cancer affects more than 54,000 Americans annually, and 13,000 die of this disease in the US each year. Kidney cancer is the eighth leading cause of cancer death in the US.1 Patients who present with localized kidney cancer have a 95% survival rate for 5 to 10 years, whereas patients who present with advanced disease have only an 18% chance for a 2-year survival.2

Kidney cancer is not a single disease; it is comprised of several different types of cancer that occur in the kidney. Each of these cancers has a different histology and clinical course, responds differently to therapy, and is caused by a different gene mutation.3, 4

Inherited Forms of Kidney Cancer

Kidney cancer is similar to other cancers, such as prostate, colon, and breast cancers, in that it occurs in both sporadic (nonfamilial) and hereditary forms. Study of families with specific types of inherited kidney cancer has led to the identification of 4 high-risk susceptibility genes for kidney cancer and has provided the foundation for the development of therapies that target these cancer gene pathways.5 There are 4 well described types of inherited kidney cancer: 1) von Hippel-Lindau (VHL), the inherited form of clear cell renal cell carcinoma (RCC); 2) hereditary papillary RCC (HPRC), the hereditary form of type 1 papillary RCC; 3) Birt-Hogg-Dube (BHD), the inherited form of chromophobe, oncocytic hybrid RCC, and 4) hereditary leiomyomatosis RCC (HLRCC) (Fig. 1).

Figure 1.

Kidney cancer is comprised of several different types of cancer, each with a different histologic type, with a different clinical course, responding differently to therapy, and caused by different genes. The VHL gene is the gene for von Hippel-Lindau and for sporadic clear cell kidney cancer. The MET proto-oncogene is the gene for hereditary papillary renal cell carcinoma and reportedly is mutated in a subset of type 1 papillary renal tumors (13%).37 The fumarate hydratase (FH) gene is the gene for hereditary leiomyomatosis renal cell carcinoma; to our knowledge, the genetic basis of sporadic, type 2 papillary kidney cancer remains to be determined. The BHD gene is the gene for the hereditary form of chromophobe kidney cancer and oncocytoma associated with Birt-Hogg-Dube. BHD gene mutations have been identified in sporadic chromophobe kidney cancer66; however, the primary genetic basis of sporadic chromophobe kidney cancer and oncocytomas remains to be determined. Reproduced with permission from Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol. 2003;170:2163-2172.

von Hippel-Lindau: Inherited Form of Clear Cell Kidney Cancer—VHL Gene

VHL is an inherited form of kidney cancer in which affected individuals are at risk for the development of tumors in several organs, including bilateral, multifocal clear cell kidney cancers6; pancreatic cysts and neuroendocrine tumors7; pheochromocytoma8; retinal angiomas9; central nervous system (CNS) hemangioblastomas10; and tumors in the inner ear (endolymphatic sac tumors).11 Patients with VHL are at risk of developing of up to 600 tumors per kidney.6 The goal of surgical management for VHL-associated kidney tumors is to prevent metastasis while preserving renal function. An approach has been developed to recommend surgical removal of renal tumors12-17 with partial nephrectomy when the largest tumor reaches 3 cm in size.18 The use of laparoscopic partial nephrectomy as well as robotic-assisted partial nephrectomy17 has the potential to reduce morbidity significantly for patients with VHL-associated renal tumors (Fig. 2).

Figure 2.

The VHL gene is the gene for clear cell kidney cancer. The VHL protein targets hypoxia-inducible factor (HIF) for ubiquitin-mediated degradation. (A) When the VHL gene is mutated in clear cell kidney cancer, the VHL protein cannot target and degrade HIF. HIF overaccumulates and causes increased transcription of downstream genes, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). (B) Future approaches could include agents that target HIF directly. (C) Current therapeutic approaches include antibodies, such as bevacizumab, that target VEGF, as well as agents, such as sunitinib and sorafenib, that target the VEGF and PDGF receptors. RCC indicates renal cell carcinoma; CUL2, cullin 2; Rbx1, ring box 1; Glut-1, glucose transporter type 1. Reproduced with permission from Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol. 2003;170:2163-2172.

Identification of the VHL Gene

Genetic linkage analysis in VHL kindreds led to the localization and subsequent identification of the VHL gene.19VHL gene mutation is identified consistently in the germline of affected patients.20 The VHL gene is also the gene for the common form of sporadic, nonhereditary, clear cell kidney cancer.21, 22 The VHL protein forms a complex with other proteins and targets the hypoxia-inducible factors (HIF) for ubiquitin-mediated degradation. HIF is a transcription factor that drives the downstream expression of several growth and proangiogenic factors that are important in cancer, such as vascular endothelial growth factor (VEGF), transforming growth factor‒α, platelet-derived growth factor (PDGF), and the epidermal growth factor receptor (EGFR). When the VHL gene is mutated, both in patients with VHL and in patients with clear cell RCC, the VHL complex cannot degrade HIF, and HIF accumulates. The result is increased levels of VEGF, PDGF, EGFR, and other downstream factors in clear cell RCC.

Hereditary Non-von Hippel-Lindau Clear Cell Renal Cell Carcinoma

Several families have been reported in which affected individuals bearing a balanced, constitutional translocation of a segment of chromosome 3 (to chromosome 8,23 chromosome 6,24 or chromosome 225) are at risk for the development of bilateral, multifocal clear cell kidney cancer. This represents an example of a “3-hit” model of kidney cancer in which the first alteration is the germline balanced translocation of chromosome 3, the second alteration is somatic loss of the chromosome 3 translocate (bearing 1 copy of the VHL gene), and the third alteration is the somatic mutation of the sole remaining allele of the VHL gene.26 Clear cell kidney cancer in the chromosome 3 translocation families tends to be later onset than in VHL, most likely because of the requirement for 3 events (non-VHL familial clear cell RCC) versus the need for 2 mutations in VHL. In a non-VHL family in which multiple members are affected with clear cell kidney cancer, a germline karyotype is recommended to rule out the possibility of a chromosome 3 translocation.

Targeting the VHL Gene Pathway in Clear Cell Renal Cell Carcinoma

Understanding the VHL gene pathway has provided the foundation for the development of targeted approaches in the treatment of patients with advanced kidney cancer. In a phase 3 randomized study in patients with untreated metastatic clear cell RCC, treatment with sunitinib resulted in superior progression-free survival and overall survival compared with interferon. Sunitinib, a tyrosine kinase inhibitor (TKI) that targets the VEGF and PDGF receptors, has been associated with nearly a 35% response rate in patients with advanced clear cell RCC and with increased progression-free survival over interferon.27, 28 Sorafenib, another TKI that targets the VEGF and PDGF receptors as well as Raf, produced partial response rates that ranged from 2% to 10% and, in patients with cytokine-refractory disease, demonstrated a doubling of the time to progression versus placebo.29 The mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, which indirectly targets the VHL pathway by inhibiting the transcription of HIF, produced a partial response rate of 9% in patients with advanced clear cell kidney cancer and increased progression-free survival and overall survival versus interferon in patients with advanced RCC who demonstrated ≥3 predefined “poor prognosis” features.30 Although to our knowledge there are few reported complete responses with these agents, and most patients eventually develop progressive disease, these initial approaches offer proof of principle of the efficacy of targeting the VHL pathway in VHL−/− clear cell kidney cancer.

Hereditary Papillary Renal Cell Carcinoma: Type 1 Kidney Cancer—MET Gene

Hereditary papillary renal carcinoma (HPRC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal, type 1 papillary RCC.31 To identify the HPRC gene, families were studied and genetic linkage analyses were performed to localize the HPRC gene to the long arm of chromosome 7. Subsequently, the MET gene was identified as the gene for HPRC.32 The MET gene encodes the cell surface receptor for hepatocyte growth factor. MET is a proto-oncogene; previously identified HPRC-associated mutations constitutively activate the tyrosine kinase domain of MET. HPRC is autosomal dominant and highly penetrant; ie, affected individuals are highly likely to develop bilateral, multifocal, papillary kidney cancer.33 HPRC kidney cancer is uniformly type 1 papillary RCC34; the estimated prevalence of renal tumors is 1100 to 3400 microscopic papillary tumors in a single kidney.35 Although HPRC is typically late onset (age of onset in the fifth, sixth, and seventh decades), an early onset form recently has been described in which the disease appears in the second and third decades.36MET gene mutations also have been detected in a subset of tumors from patients with sporadic, type 1 papillary RCC.37

Clinical Evaluation of Patients With Bilateral, Multifocal, Papillary Renal Cell Carcinoma

Germline MET mutation analysis is recommended for patients with bilateral, multifocal papillary RCC as well as for those with a family history of type 1 papillary RCC. Family history should be obtained, although this disease can be occult and late onset. Imaging assessment includes contrast-enhanced computed tomography or magnetic resonance imaging studies. HPRC renal tumors typically are relatively hypovascular, enhance uniformly, and grow slowly. Computed tomography is preferable to ultrasound for screening, because ultrasound easily can miss HPRC tumors.38

Clinical Management of Patients With Hereditary Papillary Renal Carcinoma

HPRC kidney cancers tend to be occult and, if not detected and treated, can spread to other organs. Parenchymal sparing surgery (partial nephrectomy) is recommended when the largest renal tumor approaches 3 cm in size. Patients who have tumors <3 cm generally are managed with observation.13, 39 The goal of management is to maintain the patient's renal function while minimizing the risk for metastasis.

Systemic Therapy: Targeting MET in Papillary Renal Cell Carcinoma

There are several potential approaches to targeting the MET gene pathway that currently are under study. One approach involves the use of TKIs that target the tyrosine kinase domain of MET. Other approaches include antibodies that target hepatocyte growth factor, the ligand of the MET cell surface receptor, or antibodies that target the extracellular domain of MET and inactivate the receptor. A phase 2 study of the dual MET-VEGF receptor 2 TKI GSK1363089 (formerly XL880) in patients with papillary RCC currently is underway and is the first trial to evaluate MET inhibition in this disease. In an interim analysis of that clinical trial, GSK1363089 demonstrated antitumor efficacy in patients with papillary kidney cancer.40

Birt-Hogg-Dube: Chromophobe Kidney Cancer—BHD Gene

Birt-Hogg-Dube (BHD) is an inherited renal cancer syndrome in which affected individuals are at risk for the development of cutaneous lesions (fibrofolliculoma)41; pulmonary cysts and spontaneous pneumothorax; and bilateral, multifocal kidney cancer.42 In describing the renal tumors in BHD patients, Pavlovich et al observed that 44 of 130 tumors (34%) were chromophobe kidney cancer, 50% were hybrid oncocytic tumors (areas reminiscent of chromophobe kidney cancer as well as oncocytomas), and 9% were clear cell RCC. Approximately 58% of their patients had microscopic oncocytosis identified in the remaining, macroscopically normal renal parenchyma.43 In that study, the size of the tumors at presentation was correlated with the increasing malignant potential of the histologic type. Hybrid tumors averaged 2.2 cm in size, chromophobe renal carcinomas averaged 3 cm in greatest dimension, and clear cell renal carcinomas averaged 4.7 cm. These various histologies can be observed in the same family, in the same patient, and sometimes even in the same kidney. In 1 patient, 2 oncocytomas, 7 hybrid tumors, chromophobe renal carcinomas, and 1 clear cell renal carcinoma were identified. Less than 15% of that patient's kidney was unaffected by tumor nodules.43 In an initial report of 127 patients from 45 BHD families who were screened at the National Cancer Institute, 27% had renal tumors identified.44 Because of the bilateral, multifocal nature of BHD-associated kidney cancer, a management approach involving observation of small tumors until they reach 3 cm in size often is recommended.44 When surgical intervention is recommended, an attempt is made to remove all or most of the visible tumors. Although surgical management is not considered “curative” for BHD-associated RCC, BHD-associated renal tumors often are slow growing, and only infrequently are multiple surgical procedures required during a patient's lifetime to control the tumor burden and prevent the development of metastasis.

Identification of the BHD Gene

To identify the susceptibility gene for BHD syndrome, affected individuals and their family members were evaluated by a multidisciplinary team in the Clinical Center at the National Institutes of Health. Genetic linkage analysis was performed, and the BHD gene was localized45 and then identified on the short arm of chromosome 17.46 Sequence analysis of the BHD gene (also known as folliculin [FLCN]) in the germline of affected individuals from BHD families has identified mutation of this gene in nearly 90% of affected families.46, 47 A Clinical Laboratory Improvement Amendments genetic test is available for individuals or families who are at risk for BHD syndrome.

BHD (FLCN) Gene Function

When BHD was identified, it was a novel gene with an unknown function. Subsequent studies that have identified binding partners to the protein product of the BHD gene (FLCN)48, 49 have placed this gene in a pathway involving AMP-activated protein kinase (AMPK), serine/threonine protein kinase LKB1, tuberous sclerosis complex 1 (TSC1)/TSC2, and mTOR. Those studies suggested that FLCN may be involved in nutrient and/or energy sensing through the AMPK/mTOR pathway.48

Vocke et al evaluated 77 renal tumors from 12 patients who had germline mutations of the BHD gene by DNA sequencing to identify somatic mutations in the second (wild-type) copy of the gene.50 Mutations or loss of heterozygosity of the second allele was identified in 70% of renal tumors, suggesting that BHD is a loss-of-function, tumor suppressor gene.

Targeting the BHD Gene Pathway

To asses the phenotypic effect of BHD gene mutations in the kidney and to provide a model for the evaluation of potential molecular therapeutic approaches for the treatment of BHD syndrome, a kidney-targeted BHD knockout mouse model was developed by Baba et al.51 In that rodent model, the BHD knockout mice developed enlarged, polycystic kidneys and died of renal failure at a very early age. Treatment with rapamycin had a significant impact on reducing the kidney size and increasing the median survival of the animals.51 Those studies provide the foundation for a potential therapeutic approach to BHD-associated kidney cancer.

Hereditary Leiomyomatosis Renal Cell Carcinoma: The Fumarate Hydratase Gene

Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and kidney cancer.52 Cutaneous leiomyomas most often are present on the trunk or extremities. The lesions often are unilateral, and from 10 to 100 have been observed in a single individual. Most patients will experience pain or paresthesia in association with these lesions. A high percentage of women (nearly 100%) who either have cutaneous leiomyoma or are fumarate hydratase (FH) mutation carriers develop uterine leiomyomas (fibroids). The uterine leiomyomas often are multiple and early onset; a high percentage of affected individuals reported hysterectomy or myomectomy in their 20s.53 Cutaneous and uterine leiomyosarcoma have been reported rarely.53, 54

Hereditary Leiomyomatosis Renal Cell Carcinoma-associated Kidney Cancer

HLRCC-associated kidney cancer is an aggressive form of kidney cancer that has a predisposition to metastasize early.55 The morphologic spectrum of HLRCC is unique and may be tubulopapillary, solid, often with microcystic features. The most notable histologic features may include the presence of large nuclei with prominent orangiophilic nucleoli.56 The histologic pattern can be suggestive of either type 2 papillary kidney cancer or collecting duct carcinoma. In a patient with a “collecting duct carcinoma” or “type 2 papillary kidney cancer” who has a family history of early onset uterine leiomyomas or cutaneous leiomyomas, HLRCC should be considered in the differential diagnosis. HLRCC patients are at risk for developing renal cysts and tumors that appear to develop either independently or within the renal cysts. The renal carcinomas can be early onset and infrequently are bilateral and multifocal. When HLRCC renal tumors are detected, early surgical intervention is strongly recommended.

Fumarate Hydratase: The Hereditary Leiomyomatosis Renal Cell Carcinoma Gene

The susceptibility gene for HLRCC encodes the Krebs cycle enzyme, FH.57 Mutations of the FH gene have been detected in >90% of HLRCC kindreds.53, 58 Loss of heterozygosity is observed frequently in HLRCC-associated kidney cancers,52, 56 suggesting that the FH gene has the characteristics of a tumor suppressor gene. In patients who have a history of multiple cutaneous leiomyomas and/or early onset uterine leiomyomas, germline FH mutation analysis often is recommended.55 Isaacs et al demonstrated a novel mechanism whereby the inactivation of FH was associated with a VHL-independent dysregulation of HIF, providing the foundation for a potential therapeutic approach to the treatment of HLRCC-associated kidney cancer.59 Further studies are underway to understand the relation between dysregulation of the Krebs cycle and tumorigenesis and the role of FH mutation in RCC.

Hereditary Paraganglioma/Pheochromocytoma

Hereditary paraganglioma/pheochromocytoma, an autosomal-dominant hereditary condition in which affected individuals are at risk for the development of pheochromocytoma and extra-adrenal pheochromocytomas (paragangliomas) (PGL), is characterized by germline mutation of 3 of the 4 genes that encode the Krebs cycle gene, succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD.60, 61 In 2004. Vanharanta et al identified kidney cancer as a component of the hereditary PGL complex.61 Recently, Ricketts et al reported 3 patients with either early onset or bilateral, multifocal clear cell or chromophobe renal carcinoma who had germline mutations of SDHB.62 In patients with early onset or bilateral, multifocal clear cell or chromophobe kidney cancer, consideration should be given to succinate dehydrogenase germline mutation testing.

Tuberous Sclerosis Complex

TSC is a hereditary condition in which affected individuals are at risk for the development of several manifestations, including bilateral, multifocal renal lesions. Whereas most TSC renal lesions are angiomyolipoma, RCC has been reported in 1% to 3% of individuals with TSC.63 The predominant management issue with TSC-associated angiomyolipoma revolves around the potential for spontaneous hemorrhage. Most clinicians manage TSC-associated renal angiomyolipomas with observation, surgical removal, or embolization. The management approach depends on the size and location of the tumor and the concern about the potential for spontaneous hemorrhage. Many clinicians recommend emoblization of TSC-associated renal angiomyolipomas, particularly those that measure >4 cm to 8 cm in size.63, 64 In a recent report of an open-label, phase 1/2 trial of sirolimus in patients with TSC or the related condition, lymphangioleiomyomatosis, treatment with sirolimus, which suppresses mTOR signaling, was associated with a reduction of angiomyolipoma volume of 30% in 5 patients on the study.65


Understanding the genetic basis of kidney cancer has provided the foundation for the development of therapeutic approaches targeting the kidney cancer genes. Encouraging progress has been made with agents such as sunitinib, sorafenib. and temsirolimus targeting the VHL gene pathway in clear cell kidney cancer. Studies currently are underway evaluating the role of agents that target the MET gene, in both HPRC and in sporadic, noninherited papillary RCC. Encouraging preclinical studies have provided a basis for potential therapeutic trials in BHD-associated kidney cancer as well as chromophobe renal carcinoma. Study of the FH pathway has provided an approach to the treatment of HLRCC-associated kidney cancer that also may be of benefit to patients with nonfamilial type 2 papillary kidney cancer. Knowledge of the mutations and pathways underlying each form of RCC has enabled the development of targeted approaches to treat the various types of kidney cancer, both hereditary and sporadic.


The questions and discussion below follow from the oral presentation given at the Third Cambridge Conference on Innovations and Challenges in Renal Cancer and do not correspond directly to the written article, which is a more general review.

Dr. Michael Atkins: Dr. Linehan, in your long-term treatment protocols, have you seen any chronic side effects, any other problems in other organs, or any resistance that develops in the kidney tumors?

Dr. W. Marston Linehan: Our longest experience is about 12 months. People with localized disease do not like being on the drug this long. They can develop diarrhea and fatigue, and it is inconvenient.

Dr. Atkins: Do you see any changes in the other aspects of these hereditary diseases besides those that you described within the kidney tumors?

Dr. Linehan: For hereditary papillary renal carcinoma, they only get kidney tumors. For VHL, we are evaluating response in retinal, CNS, pancreatic, as well as kidney lesions.

Dr. Robert Figlin: Kidney cancer actually falls into the paradigm of many other diseases that are EGFR overexpressing without TKI benefit.

Dr. William Kaelin: That is right, and you could argue even at the extreme that EGFR overexpression in kidney cancer is an epiphenomenon. That is why I come back to the experiments of Stephen Lee, which were carefully done and well controlled. They suggested that if you inhibit this pathway in these cells, they do not form tumors, at least in mice. This is just 1 of those examples where the mouse model might be misleading, and there is something going on in humans that we do not understand.

Dr. Linehan: It also could be that a different agent targeting EGFR would have a different effect.

Dr. Figlin: But without VEGF receptor inhibition or VEGF inhibition, the only thing that 6474 (AZD6474, an agent which targets the VEGF and EGF receptor) answers in my mind is whether receptor and receptor inhibition is somehow different from ligand and receptor inhibition because otherwise, we know the answer to that question. It does not help.

Dr. Linehan: As we enter the era of combination therapy, it is at least formally possible that EGFR inhibitor as monotherapy might have little activity. However, in combination with some of these other active agents, you could see a response by blocking EGFR signaling.

Dr. Gary Hudes: Is there a difference in renal carcinomas in patients with VHL germline mutation tumors versus sporadic alterations in terms of responsiveness to the currently available VEGF and VEGF receptor-directed therapies?

Dr. Linehan: We do not know. Genotypically, they are identical. There are not that many people with metastatic VHL who have been treated with systemic agents.

Dr. Figlin: Do you have a series of patients with VHL in whom you have genotyped the metastases as well as the primary tumor so that you know that the genetic abnormality in the metastases was exactly the same as the genetic abnormality in the primary tumor?

Dr. Linehan: Yes, we have. For VHL, it was.

Conflict of Interest Disclosures

The program was made possible by educational grants provided by Genentech, Novartis Pharmaceuticals, Pfizer, Inc., and Wyeth Pharmaceuticals. Program management and CME sponsorship were provided by InforMEDical Communications, Inc., Carlisle, Massachusetts.

Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12,400. The content of this publication does not reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations suggest endorsement by the US Government.