Molecular Diagnosis and Therapy of Kidney Cancer*

Molecular Diagnosis and Therapy of Kidney Cancer

W. Marston Linehan, M.D., Gennady Bratslavsky, Peter A. Pinto, Laura S. Schmidt, LenNeckers, Donald Bottaro, and Ramaprasad SrinivasanUrologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, Basic ResearchProgram, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702

AbstractKidney cancer is not a single disease; it is made up of a number of cancers that occur in thekidney, each with a different histology, having a different clinical course, responding differently totherapy and caused by a different gene. Understanding the genetic basis of cancer of the kidneyhas significant implications for diagnosis and management of this disease. The VHL gene is thegene for clear cell kidney cancer. The VHL protein forms a complex that targets the hypoxiainducible factors for ubiquitin-mediated degradation. Knowledge of this pathway has provided thefoundation for the development of a number of novel therapeutic approaches that have beenapproved by the FDA for treatment of this disease. The MET gene is the gene for the hereditaryform of type 1 papillary renal carcinoma and has been found to be mutated in a subset of sporadictype 1 papillary kidney cancers. Clinical trials are currently ongoing with agents targeting thetyrosine kinase domain of MET in sporadic and hereditary forms of papillary kidney cancer. TheBHD gene is the gene for the hereditary type of chromophobe kidney cancer. The BHD gene isthought to be involved in energy and/or nutrient sensing through the AMPK and mTOR signalingpathways. Hereditary Leiomyomatosis Renal Cell Carcinoma, a hereditary form of type 2papillary renal carcinoma, is caused by inactivation of the Krebs cycle enzyme, fumaratehydratase (fumarase, FH). Loss of FH activity has been shown to alter the degradation of hypoxiainducible factor (HIF) in a VHL-independent fashion. Knowledge of these kidney cancer genepathways has enabled new approaches for the management of this disease and has provided thefoundations for the development of targeted therapeutics for this disease.

Keywordskidney neoplasms; VHL; MET; BHD; TSC1; TSC2; fumarate hydratase succinate dehydrogenase

IntroductionThere are over 57,000 cases of kidney cancer in the United States annually and nearly13,000 die of this disease each year.(32) Kidney cancer is the seventh most common cancerin men and the ninth most common cancer in women.(32) Unlike other genitourinarymalignancies, the incidence of kidney cancer is rapidly increasing at 2.5 percent per year.The incidence of kidney cancer can only partly be explained by the increased use of imagingmodalities such as MRI, computed tomography and ultrasound.(8) While there was anincreased incidence for localized disease, increases were also noted for advanced disease.

Correspondence: W. Marston Linehan, M.D., Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bldg10 CRC Rm 1-5940, Bethesda, Maryland 20892-1107, Tel: (301) 496-6353, Fax: (301) 402-0922, [email protected] Statement: The authors have no conflicts of interest to disclose.

NIH Public AccessAuthor ManuscriptAnnu Rev Med. Author manuscript; available in PMC 2011 January 1.

Published in final edited form as:Annu Rev Med. 2010 ; 61: 329–343. doi:10.1146/annurev.med.042808.171650.

NIH

-PA Author Manuscript

NIH


NIH


The mortality rate for this disease is also increasing, suggesting that the increasing incidenceis not driven by increased detection of small tumors alone.(8)

Kidney cancer is not a single disease; it is made up of a number of different types of cancerthat occur in the kidney; each with a different clinical course, a different histology, causedby a different gene and responding differently to therapy.(43) Patients who present with alocalized kidney tumor (TNM Stage I) have a ninety-six percent five year survival.However, patients who present with advanced disease (TNM Stage IV) have only a twenty-six percent five year survival.(41) The development of novel therapeutic approaches fortargeting the kidney cancer disease gene pathways has the potential to significantly improvesurvival for patients with advanced forms of this disease.

Identification of the Kidney Cancer GenesIn order to improve the diagnosis and management of kidney cancer and to provide thefoundation for the development of better methods for diagnosis as well as targetedtherapeutic approaches to this disease, families with kidney cancer were studied in order toidentify the genes for this disease.

Clear cell kidney cancer: von Hippel-Lindauvon Hippel Lindau (VHL) is a hereditary cancer syndrome in which affected individuals areat risk for the development of tumors in a number of organs, including the kidney. Patientswith VHL are at risk for the development of early onset, bilateral, multifocal clear cellkidney cancer. It has been estimated that VHL patients are at risk for the development of upto 600 renal tumors and 1100 cysts per kidney.(89) Historically, 35-45% of VHL patientsdied of metastatic kidney cancer. While removal of both kidneys should decrease the rate ofmetastasis; the quality of life and long-term survival would be severely impacted. Over a 20-year period an approach has been developed for the clinical management of VHL renaltumors which involves observation of small renal tumors until they reach a 3 cm sizethreshold. When the tumors reach 3 cm, surgical intervention involving a nephron-sparingapproach with partial nephrectomy is utilized.(87,89) After 10 years of follow-up, no patientwith VHL with a renal tumor ≤ 3 cm managed in this fashion had been found to havedeveloped metastatic disease.(25) Renal parenchymal sparing therapy with preservation ofrenal function with close observation for recurrence is recommended whenever possible.(13)

Identification of the VHL geneGenetic linkage analysis was performed in VHL families to identify the clear cell kidneycancer gene. The VHL gene was identified on the short arm of chromosome 3 and mutationof this gene was found in the germline of individuals affected with von Hippel Lindau.(38)With improved detection methods mutation of the VHL gene is now found in nearly 100% ofVHL families.(75)

VHL is the clear cell kidney cancer geneWhen tumor tissue from patients with kidney cancer was tested for alteration of the VHLgene, mutations were detected in a high percentage of patients with clear cell kidney cancer.(20) No mutations of the VHL gene were detected in tumors from patients with papillary,chromophobe or collecting duct kidney cancer or oncocytoma. Nickerson, et al. detectedmutation or methylation of the VHL gene in 91% of tumors from patients with clear cellkidney cancer.(52)

Linehan et al. Page 2

Annu Rev Med. Author manuscript; available in PMC 2011 January 1.

NIH


NIH


NIH


VHL gene pathwayThe VHL gene protein (would it be better to say ‘VHL protein’ or ‘VHL gene product’?)forms a complex with elongin B and elongin C and Cul2.(12,37,58) and targets the hypoxiainducible factors, HIF1α and HIF2α, for ubiquitin mediated degradation. The hypoxiainducible factors (HIF) are transcription factors that regulate the transcription of a number ofother genes such as vascular endothelial growth factor (VEGF), platelet derived growthfactor (PDGF), epidermal growth factor receptor (EGFR) and the glucose transporter,GLUT1. When there is normoxia, the VHL complex targets HIF for ubiquitin-mediateddegradation, while during a hypoxia, the complex does not target and degrade HIF, allowingHIF to accumulate and drive the transcription of the downstream HIF-dependent genes.When there is mutation of the VHL gene in clear cell kidney cancer, either in the alphadomain that binds elongin C/B and Cul2, or in the beta domain that targets HIF fordegradation,(73) HIF is not degraded and over-accumulates. The result is the increasedtranscription of such HIF downstream genes as VEGF, PDGF, EGFR and GLUT1.(31,35,45,54,55,73)

Targeting the VHL gene pathway in clear cell renal carcinoma: VEGFBevacizumab—The first trial to target the VHL gene pathway in clear cell renal carcinomawas with bevacizumab, an anti-VEGF antibody, which was evaluated in patients withadvanced clear cell renal carcinoma. In this three arm randomized trial, patients treated withhigh dose bevacizumab had a significantly increased progression free survival comparedwith those treated with placebo.(92) This was the first trial to show a clinical effect inadvanced clear cell kidney cancer with an agent targeting the VHL pathway.

Sorafenib—Sorafenib is a small molecule inhibitor which targets the tyrosine kinasedomain of a number of cell surface receptors, including VEGFR and PDGFR, as well as theintracellular signaling enzyme, raf kinase.(91) When Sorafenib was evaluated in arandomized phase III study as a second line agent in patients with advanced clear-cell renalcell carcinoma, there was a 10% partial response and an increase in disease free progressionfrom 2.8 months to 5.5 months compared to placebo.(14) Final analysis of the studyrevealed no difference in overall survival between the sorafenib and placebo group;however, when the post-cross-over placebo survival data was censored, there was anincrease in survival in the sorafenib arm.(15) Sorafenib is frequently used as a second lineagent in patients who progress while on sunitinib.

Sunitinib—Sunitinib is another small molecule receptor tyrosine kinase inhibitor whichhas direct antitumor as well as antiangiogenic effects. This agent has activity against thevascular endothelial growth factor receptor (VEGFR), the platelet derived growth factorreceptor (PDGFR) and the KIT receptor.(46) In patients with metastatic clear cell kidneycancer sunitinib has been found to have a response rate of 31%, with a progression freesurvival of 11 months. In a randomized phase III trial sunitinib has been shown to improveprogression free survival compared to treatment with interferon (median 11 months vs. 5months); a recent analysis of mature data from this trial also suggests that patientsrandomized to the sunitinib had superior overall survival (median 26.4 months vs. 21.8months, p=0.051). Treatment with sunitinib is associated with side effects common to thisclass of agents, such as fatigue, hand-foot syndrome, diarrhea, hypertension andhypothyroidism.(50) Sunitinib is often used as a first line agent in patients with advancedclear cell kidney cancer.

Axitinib—Axitinib is an oral small molecule tyrosine kinase inhibitor of vascularendothelial receptors VEGFR1, VEGFR2 and VEGFR3. In a Phase II trial of Axitinib in 52patients with advanced kidney cancer, Rixe, et al. observed a partial response in 40%



NIH


NIH


NIH


(21/52), a complete response in 4% (2/52), a median time to progression of 15.7 months anda median survival of 29.9 months. Most patients treated on this study displayed some tumorshrinkage and many had been pre-treated with either IL-2 or interferon. The response profileof these patients compares favorably with those from other antiangiogenesis trials; however,60% of patients developed diarrhea, 58% hypertension, 52% experienced fatigue, 44%reported nausea, and 37% developed hoarseness. Treatment related proteinuria was observedin 4/52 patients.(62) The approach directed at a single type of growth factor receptor has thepotential to provide a strategy for precisely targeting the VHL pathway in clear cell kidneycancer while decreasing the toxicity of multikinase inhibitors.(40)

Targeting the VHL gene pathway in clear cell renal carcinoma: mTORTemsirolimus—The mTORC1 pathway regulates the expression and stability of HIF1α.In preclinical models, growth arrest caused by agents which target mTOR correlate with theblock in translation of mRNA encoding HIF1α.(28,77) Hudes, et al. evaluated the effect oftemsirolimus, interferon or the combination of both in patients with previously untreated,poor-prognosis metastatic renal cell carcinoma. Eighty percent of the patients in this trialhad clear cell kidney cancer. The response rate to temsirolimus was 8.6%, the progressionfree survival in the temsirolimus treated patients was 3.8 months versus 1.9 months in theinterferon treated patients (p=0.0001) and the overall survival was 10.9 months in thetemsirolimus treated patients versus 7.3 months in the patients treated with interferon(p=0.0069).(27)

Everolimus—Everolimus, another orally administered small molecule inhibitor of themammalian target of rapamycin (mTOR), was evaluated in a phase III, randomized, double-blind, placebo-controlled trial in 410 patients with metastatic kidney cancer who hadprogressed on sunitinib or sorafenib therapy. There was a 1% response rate in theeverolimus patients and a progression free survival of 4.0 months in the everolimus armversus 1.9 months in the placebo arm. The overall survival in the placebo arm was 8.8months; median overall survival in the everolimus patients had not been reached.(48)Everolimus may be considered in patients who have failed VEGF-targeted agents (Figure 1).

Combinations of Agents Targeting the VHL PathwayTrials are currently under way to evaluate the role of combinations of therapeutic agentswhich target the VHL pathway(17,49,57) as well as the role of sequential therapy in kidneycancer. The combined toxicity of targeted agents can be significant and dose reduction isoften required. While there is evidence that administering targeted agents sequentiallyprovides clinical benefit and prolongs progression-free survival, data on overall survivalawaits the results of trials currently in progress.(16)

Targeting the VHL pathway: neoadjuvant (presurgical) therapy for clear cell kidney cancerThe standard of care for patients with metastatic kidney cancer has been cytoreductivenephrectomy prior to administration of systemic therapy.(18,86) The clinical approachinvolves an assessment of the patient's clinical condition and the extent of the metastaticdisease. In general, at the National Cancer Institute, if a patient has more disease in thekidney than outside the kidney, cytoreductive nephrectomy followed by systemic therapy isrecommended. If the patient has more disease outside the kidney or has rapidly progressivedisease, initial systemic therapy is recommended.(85) This approach has largely beenextended to studies involving targeted therapeutics, where the majority of patients onclinical trials have previously had a cytoreductive nephrectomy.

While there are no completed randomized prospective studies addressing the role of theneoadjuvant therapy in setting of metastatic RCC, a few retrospective series have described



NIH


NIH


NIH


the use of neoadjuvant targeted therapy in patients with their primary kidney tumor in place.Van der Veldt, et al observed a partial response in 4/17 patients who had been treated withsunitinib prior to cytoreductive nephrectomy. There was a 31% volume reduction in theprimary tumor of responding patients.(82) Shuch, et al. reported on four patients who weregiven neoadjuvant targeted therapy. These patients had shrinkage of tumor thrombus in theinferior vena cava, in retroperitoneal nodes and in a renal fossa recurrence.(70) Karakiewiczet al. reported a dramatic down-staging of a thrombus in the right atrium in a 75 year oldwoman treated with two cycles of sunitinib.(36)

Margulis, et al. evaluated the surgical parameters and perioperative complications of 44patients treated with targeted molecular therapies before either cytoreductive nephrectomyor resection of renal cell carcinoma recurrence with a matched cohort of patients withmetastatic kidney cancer who had up front cytoreductive nephrectomy. They found nosignificant difference between the incidence of perioperative mortality, re-exploration,cardiovascular, thromboembolic or other surgical complications between the two groups.(44) Potential advantages of neoadjuvant therapy include tumor downsizing and earlyinstitution of systemic therapy, as well as identification of those patients who do not respondto therapy and could be spared a morbidity of a cytoreductive nephrectomy. Alternatively, itis possible that patients who undergo cytoreductive nephrectomy up front will respond betterto therapy than those who receive neoadjuvant therapy, followed by cytoreductivenephrectomy and subsequent resumption of systemic therapy. Controlled trials willdetermine the role of neoadjuvant therapy in the setting of metastatic kidney cancer inpatients with their primary kidney cancer in place.

Targeting the VHL pathway: adjuvant therapy for clear cell kidney cancerThe 5 year survival rate for patients who present with locally advanced kidney cancer (TNMStage III) is 40 to 60% and 20 to 40% of patients who undergo surgical resection forclinically localized disease will experience either a local or systemic recurrence.(22) Theadvent of a number of novel targeted molecular therapeutic approaches in the treatment ofclear cell kidney cancer raises the possibility that adjuvant therapy may be beneficial forpatients with high risk/locally advanced kidney cancer who have undergone completesurgical resection. A number of clinical trials are underway to determine whether or notadjuvant targeted therapy will be beneficial to patients with high risk localized or locallyadvanced kidney cancer. The ECOG intergroup trial (ASSURE) randomizes patients withclear and non-clear cell kidney cancer to receive either 1 year of sunitinib, sorafenib orplacebo. The MRC trial (SORCE) randomizes patients with clear and non-clear cell kidneycancer to receive either placebo (3 years) or sorafenib (1-3 years). The Pfizer trial (S-TRAC)randomizes patients with clear cell kidney cancer to receive sunitinib versus placebo for 1year. The Wilex trial (ARISER) randomizes patients to receive G250 monoclonal chimericantibody versus placebo.

Imaging the VHL PathwayCarbonic Anhydrase 9 (CA9) is Regulated by VHL—In 1998 investigators in thelaboratory of Michael Lerman at the National Cancer Institute, using RNA differentialdisplay to study genes in the VHL pathway, found that the carbonic anhydrase genes, CA9and CA12, were regulated by the VHL protein. Mutation of the VHL gene was found to up-regulate these transmembrane enzymes which are critical for the regulation of pH in theextracellular microenvironment.(30) Kaluz et al. recently reported that carbonic anhydrase 9is tightly regulated by the transcriptional activity of HIF1α and is one of the most sensitiveendogenous sensors of its activity.(34)



NIH


NIH


NIH


Functional Imaging with G250, an Antibody that Recognizes CA9—G250, anantibody that has high binding affinity for clear cell kidney cancer(74), has been shown torecognize the epitope of carbonic anhydrase 9.(81) Bui et al. showed that CA9 expression isfound in more than 94% of clear cell kidney cancers.(5,6,81) Divgi et al. conducted a studyusing an 124I-labelled chimeric G250 antibody (124I-cG250) to perform pre-operativecharacterization of clear cell kidney cancer and accurately identified 15 of 16 clear cellkidney cancers by 124I-cG250 PET scanning. This study clearly delineated clear cell renalcarcinoma from other types of kidney tumors and provides a potential alternative to tumorbiopsy.(11) This technique provides a potential molecular diagnostic to differentiate tumorswith VHL gene mutations from other types of kidney cancer.

Type I Papillary Renal Carcinoma: Hereditary Papillary Renal Carcinoma—Hereditary Papillary Renal Carcinoma (HPRC) is an inherited cancer syndrome in whichaffected individuals are at risk for the development of bilateral, multifocal type 1 papillaryrenal carcinoma.(94) Genetic linkage was performed in HPRC families and the MET geneon chromosome 7 was found to be the HPRC gene.(65) Activating mutations in the tyrosinekinase domain of MET are found in the germline of affected individuals in HPRC families.The renal tumors in HPRC patients are highly penetrant, and it is estimated that an HPRCpatient who lives to 80 has a nearly 90% likelihood of developing kidney cancer.(67) Theseindividuals are at risk for the development of up to 3400 microscopic papillary tumors perkidney.(56) The management approach for HPRC patients is similar to that in VHL patients;active surveillance is recommended until the largest tumor reaches the 3 cm threshold.(7,25)

Targeting the MET gene pathway in type 1 papillary kidney cancer—Amulticenter Phase II clinical trial is currently underway evaluating the role of GSK'089(foretinib), an oral dual kinase small molecule agent which targets the tyrosine kinasedomains of MET as well as VEGFR2, in patients with sporadic as well as hereditarypapillary kidney cancer. Activity has been observed with this agent in papillary RCC,notably in tumors with MET mutations (Figure 2).(71)

Chromophobe Kidney Cancer: Birt-Hogg-Dubé—Birt-Hogg-Dubé (BHD) is aninherited cancer syndrome in which affected individuals are at risk for the development ofbenign cutaneous lesions (fibrofolliculomas), pulmonary cysts and renal tumors.(93) BHDpatients are at risk for the development of bilateral, multifocal chromophobe, hybridoncocytic and clear cell renal cell carcinomas and oncocytomas.(59) Genetic linkageanalysis was performed in BHD kindreds to identify the BHD gene on chromosome 17.(53)Germline BHD gene mutations have been found in over 90% of BHD kindreds.(68,80) TheBHD gene has the classic characteristics of a loss of function, tumor suppressor gene.(84)

Targeting the BHD pathway in chromophobe kidney cancer—The product of theBHD gene, folliculin (FLCN), forms a complex with two FLCN interacting proteins, FNIP1and FNIP2, which bind AMPK, a key molecule for energy sensing that negatively regulatesmTOR activity.(2,23) The BHD gene is thought to be involved in energy sensing throughthe AMPK and mTOR pathways.

In order to develop a model to evaluate agents which target the BHD pathway, a mousemodel was developed in which the BHD gene was selectively knocked out in the kidneys.Affected mice developed enlarged, polycystic kidneys and died from renal failure by 3weeks of age. Rapamycin treated mice had significantly smaller kidneys than controlanimals and their life-expectancy was nearly doubled.(1) These findings may provide arationale for the development of a targeted approach to BHD-associated chromophobe aswell as sporadic chromophobe kidney cancer.



NIH


NIH


NIH


Type 2 papillary kidney cancer: Hereditary Leiomyomatosis Renal CellCarcinoma—Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) is an inheritedcancer syndrome in which affected individuals are at risk for the development of uterine andcutaneous leiomyomas and kidney cancer.(39) HLRCC-associated kidney cancer is anunusually aggressive type of kidney cancer that has a propensity to spread, even when theprimary kidney tumor is very small.(21,47) Surveillance is not recommended in HLRCCkidney cancer; early surgical resection is recommended when an HLRCC renal tumor isdetected.

Targeting the fumarate hydratase gene in type 2 papillary kidney cancer—TheKrebs cycle enzyme, fumarate hydratase, is the gene for HLRCC.(78) Mutations of thefumarate hydratase gene are found in over 90% of HLRCC families.(79,90) Isaacs, et al.showed that when fumarate hydratase is inactivated, increased levels of fumarate act as acompetitive inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase. This preventsHIF hydroxylation and results in a VHL-independent mechanism for decreased degradationof HIF.(29) A more recent study has reinforced the glycolytic nature of HLRCC and hasidentified accumulation of reactive oxygen species as an additional determinant of HIFstabilization.(76) These observations provide the basis for potential therapeutic approachestargeting the HIF pathway and HIF-dependent glycolysis for HLRCC-associated renalcancers.

SDHB germline mutations and familial renal cancer—Succinate dehydrogenase isanother Krebs cycle enzyme gene that has been associated with the development of familialtumors. Familial paraganglioma/pheochromocytoma kindreds have been found to havegermline mutations in the mitochondrial complex II genes, SDHB, SDHC, and SDHB. Renalcarcinoma, along with pheochromocytoma/paraganglioma, has been found to be acomponent of the familial pheochromocytoma/paraganglioma complex(24,51,72,83) and arecent report described germline SDHB mutations in a family with renal cancer with nohistory of pheochromocytoma.(61)

Tuberous SclerosisThe tuberous sclerosis complex is an autosomal dominant disorder associated with mutationof either the TSC1 or TSC2 gene. Affected individuals are at risk for the development of anumber of neurologic, dermatologic and pulmonary manifestations as well as renalangiomyolipomas.(9) The TSC1-TSC2 complex interacts with a number of cellularpathways, including modulation of mTOR. When the cell senses energy deprivation, AMPKactivates TSC2 and mTOR activity is decreased.(9)

Renal angiomyolipomas are most often managed conservatively. Angioinfarction is oftenrecommended for tumors over 4 cm in size, although surgical resection may also beperformed if there is concern about imminent hemorrhage or if renal angiomyolipoma isfound in young women of child-bearing age.(69)

Targeting the mTOR pathway in tuberous sclerosisBissler, et al. evaluated the role of sirolimus, an agent which targets the mTOR pathway, inpatients affected with tuberous sclerosis and lymphangioleiomyomatosis. In this trial, therenal angiomyolipomas regressed during sirolimus therapy, however, they tended to increasein size after the treatment was stopped.(3)



NIH


NIH


NIH


Management of small renal masses: lessons learned from management of tumors withknown genetic alterations

Nephrectomy versus Partial NephrectomyHereditary Tumors: Since the mid 1980's the management of small renal masses inpatients with VHL, HPRC and BHD has involved observation until the largest mass reaches3 centimeters. As these patients are at risk for the development of bilateral, multifocaltumors, the use of parenchymal sparing surgery was based on a desire to maintain renalfunction as long as possible while reducing the risk for metastasis.(87,88) Using thisapproach, no patient who underwent renal parenchymal sparing surgery required renalreplacement and no patient whose tumor ≤ 3 cm was removed was found to have developedmetastasis at 10 years.(25)

Over the years organ preservation was combined with minimally invasive techniques.Laparoscopic and then robotic partial nephrectomy was found to provide minimally invasiveand nephron sparing surgical options for patients who might otherwise require open surgeryor total nephrectomy.(4,63,64)

Sporadic Tumors: The same techniques developed for patients with inherited, bilateralmultifocal renal tumors have been applied to patients with sporadic, non-inherited renaltumors. Gill et al. reported a series of 1800 patients who underwent either open orlaparoscopic partial nephrectomy. With either technique, there was excellent functional andoncologic outcome.(19) Huang, et al. recently reviewed the SEER cancer registry databaseand highlighted the increased cardiovascular morbidity associated with nephrectomy versuspartial nephrectomy and recommend partial versus total nephrectomy whenever feasible.(26)

Management of small sporadic renal tumors: intervention or surveillanceA surveillance approach for the management of small renal tumors in patients with VHL,hereditary papillary renal carcinoma (HPRC) and Birt-Hogg-Dubé (BHD) was adopted inthe 1980's. Patients with VHL (clear cell RCC), HPRC (type 1 papillary RCC) or BHD(chromophobe or hybrid oncocytic RCC) were managed expectantly when the largest renaltumor was less than 3 cm in size. When the largest tumor reached 3 cm, surgicalintervention was recommended. This approach was found to be safe and preserved renalfunction over a 20-year period. Active surveillance is not recommended in patients withhereditary leiomyomatosis renal cell cancer (HLRCC), who develop aggressive type 2papillary renal cancers. In these patients early surgical intervention is recommended.

A rational for surveillance of sporadic renal tumors comes from the experience withmanagement of hereditary renal tumors with known genetic alterations. The biologicbehavior of a hereditary renal tumor with a known genetic alteration should be no differentfrom a sporadic renal tumor with a mutation of the same gene. A clear cell renal carcinomain a patient affected with VHL has a mutation of the VHL gene as well as loss of the secondallele (i.e., biallelic inactivation of the VHL gene). A sporadic clear cell renal tumor with aVHL mutation has loss of the second allele as well (i.e., biallelic inactivation of the VHLgene). The histology of the VHL clear cell renal tumor and the histology of the sporadicclear cell renal tumor with a VHL gene mutation are identical.

There have been a number of reports on the role of active surveillance (AS) for clinicallylocalized renal masses.(10,33) Crispen reported on 172 renal tumors with a median tumordiameter of 2.0 cm in 154 patients under AS. Thirty-nine percent of the tumors underwentdelayed intervention and 84% were found to be pathologically malignant. Metastatic disease



NIH


NIH


NIH


developed in 2/154 (1.3%) patients.(10) Metastatic disease was also detected in 2% of thepatients on active surveillance in the Canadian prospective trial.(33)

A renal biopsy is now increasingly accepted for patients being considered for activesurveillance. Although some renal tumors will be found to be benign, some will be highgrade malignant tumors (type 2 papillary, collecting duct or medullary RCC) that are notsuitable for surveillance. Active surveillance is an appropriate option for selected patientswho are elderly or those with significant comorbidities. For example. in a well selectedelderly or frail patient with low grade clear cell renal carcinoma, active surveillance mightbe an appropriate option. In contrast, presence of a high grade type 2 papillary renalcarcinoma should warrant intervention, as delay in treatment may not be justified. Furtherstudies will be required to determine whether active surveillance with delayed surgicalmanagement is a safe alternative to surgical resection in younger patients.

Kidney cancer is fundamentally a metabolic disorderUnderstanding the kidney cancer gene pathways has provided the foundation for thedevelopment of targeted therapeutic approaches for this disease. Knowledge of the geneticbasis of kidney cancer has important implications for diagnosis and management of thisdisease.

Study of the genes for kidney cancer has revealed that kidney cancer is fundamentally ametabolic disorder. The seven kidney cancer genes represent disorders of energy, nutrient,iron and oxygen sensing (Figure 3). Although current approaches of targeting thedownstream HIF upregulated genes has resulted in dramatic response to therapy andincreased survival, few complete responses have been reported and most patients progress tosuccumb to the disease. Targeting the basic metabolic alterations in kidney cancer has thepotential to provide a more durable and effective approach to therapy.

Summary Points

1. Clear cell kidney cancer and kidney cancer associated with von Hippel-Lindauare caused by mutation of the VHL gene, which results in a disorder of oxygensensing.

2. Hereditary papillary renal cell carcinoma and a subset of sporadic type 1papillary kidney cancers are caused by mutation of the MET gene.

3. The hereditary form of chromophobe kidney cancer associated with Birt-Hogg-Dubé is caused by mutation of the BHD gene, which is involved with theAMPK/mTOR pathway.

4. The hereditary form of kidney cancer associated with HereditaryLeiomyomatosis Renal Cell Carcinoma is caused by mutation of the gene for theKrebs cycle enzyme, fumarate hydratase.

5. The hereditary form of kidney cancer associated with familialpheochromocytoma/paraganglioma results from mutations of the gene for theKrebs cycle enzyme, succinate dehydrogenase B.

6. The hereditary form of angiomyolipoma results from mutations of the TSC1 andTSC2 genes, which are involved in the AMPK/mTOR pathway.

7. Understanding the pathways of the kidney cancer genes has provided thefoundation for the development of targeted therapeutic approaches to thetreatment of these diseases.



NIH


NIH


NIH


Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.

AcknowledgmentsThis research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute,Center for Cancer Research. This project has been funded in part with federal funds from the National CancerInstitute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication doesnot necessarily reflect the views or policies of the Department of Heath and Human Services, nor does mention oftrade names, commercial products, or organizations imply endorsement by the U.S. Government.

The authors acknowledge the outstanding editorial and/or graphics support by Georgia Shaw and Masaya Baba,M.D., Ph.D.

Literature Cited1. Baba M, Furihata M, Hong SB, et al. Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse

model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J NatlCancer Inst 2008;100:140–54. [PubMed: 18182616]

2. Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a bindingprotein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci US A 2006;103:15552–7. [PubMed: 17028174]

3. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosiscomplex or lymphangioleiomyomatosis. N Engl J Med 2008;358:140–51. [PubMed: 18184959]

4. Boris R, Proano M, Linehan WM, et al. Robotic assisted partial nephrectomy for multiple renalmasses: feasibility and results of initial experience. J Urol. 2009 In Press.

5. Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an independent predictor of survivalin advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res2003;9:802–11. [PubMed: 12576453]

6. Bui MH, Visapaa H, Seligson D, et al. Prognostic value of carbonic anhydrase IX and KI67 aspredictors of survival for renal clear cell carcinoma. J Urol 2004;171:2461–6. [PubMed: 15126876]

7. Chernoff A, Choyke PL, Linehan WM, et al. Parenchymal sparing surgery in a patient with multiplebilateral papillary renal cancer. J Urol 2001;165:1623–4. [PubMed: 11342935]

8. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States.JAMA 1999;281:1628–31. [PubMed: 10235157]

9. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med2006;355:1345–56. [PubMed: 17005952]

10. Crispen PL, Viterbo R, Boorjian SA, et al. Natural history, growth kinetics, and outcomes ofuntreated clinically localized renal tumors under active surveillance. Cancer. 2009 Epub.

11. Divgi CR, Pandit-Taskar N, Jungbluth AA, et al. Preoperative characterisation of clear-cell renalcarcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patientswith renal masses: a phase I trial. Lancet Oncol 2007;8:304–10. [PubMed: 17395103]

12. Duan DR, Pause A, Burgess WH, et al. Inhibition of transcription elongation by the VHL tumorsuppressor protein. Science 1995;269:1402–6. [PubMed: 7660122]

13. Duffey BG, Choyke PL, Glenn GM, et al. The Relationship Between Renal Tumor Size andMetastases in Patients with von Hippel-Lindau Disease. J Urol 2004;172:63–5. [PubMed:15201738]

14. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. NEngl J Med 2007;356:125–34. [PubMed: 17215530]

15. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for Treatment of Renal Cell Carcinoma: FinalEfficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer GlobalEvaluation Trial. J Clin Oncol. 2009

16. Escudier B, Goupil MG, Massard C, et al. Sequential therapy in renal cell carcinoma. Cancer2009;115:2321–6. [PubMed: 19402067]



NIH


NIH


NIH


17. Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses ofsunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:1432–9. [PubMed:19224847]

18. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2bcompared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med2001;345:1655–9. [PubMed: 11759643]

19. Gill IS, Kavoussi LR, Lane BR, et al. Comparison of 1,800 laparoscopic and open partialnephrectomies for single renal tumors. J Urol 2007;178:41–6. [PubMed: 17574056]

20. Gnarra JR, Tory K, Weng Y, et al. Mutations of the VHL tumour suppressor gene in renalcarcinoma. Nature Genetics 1994;7:85–90. [PubMed: 7915601]

21. Grubb RL III, Franks ME, Toro J, et al. Hereditary leiomyomatosis and renal cell cancer: asyndrome associated with an aggressive form of inherited renal cancer. J Urol 2007;177:2074–80.[PubMed: 17509289]

22. Haas NB, Uzzo R. Adjuvant therapy for renal cell carcinoma. Curr Oncol Rep 2008;10:245–52.[PubMed: 18765155]

23. Hasumi H, Baba M, Hong SB, et al. Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene 2008;415:60–7. [PubMed: 18403135]

24. Henderson A, Douglas F, Perros P, et al. SDHB-associated renal oncocytoma suggests abroadening of the renal phenotype in hereditary paragangliomatosis. Fam Cancer. 2009

25. Herring JC, Enquist EG, Chernoff A, et al. Parenchymal sparing surgery in patients with hereditaryrenal cell carcinoma: 10-year experience. J Urol 2001;165:777–81. [PubMed: 11176466]

26. Huang WC, Elkin EB, Levey AS, et al. Partial nephrectomy versus radical nephrectomy in patientswith small renal tumors--is there a difference in mortality and cardiovascular outcomes? J Urol2009;181:55–61. [PubMed: 19012918]

27. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271–81. [PubMed: 17538086]

28. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1alpha expressionand function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004–14. [PubMed:12242281]

29. Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with biallelic loss of fumaratehydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell2005;8:143–53. [PubMed: 16098467]

30. Ivanov SV, Kuzmin I, Wei MH, et al. Down-regulation of transmembrane carbonic anhydrases inrenal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. Proc Natl Acad Sci U SA 1998;95:12596–601. [PubMed: 9770531]

31. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindauubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468–72.[PubMed: 11292861]

32. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2009. CA: A Cancer Journal forClinicianscaac. 2009

33. Jewett MA, Zuniga A. Renal tumor natural history: the rationale and role for active surveillance.Urol Clin North Am 2008;35:627–34. [PubMed: 18992616]

34. Kaluz S, Kaluzova M, Liao SY, et al. Transcriptional control of the tumor- and hypoxia-markercarbonic anhydrase 9: A one transcription factor (HIF-1) show? Biochim Biophys Acta2009;1795:162–72. [PubMed: 19344680]

35. Kamura T, Koepp DM, Conrad MN, et al. Rbx1, a component of the VHL tumor suppressorcomplex and SCF ubiquitin ligase. Science 1999;284:657–61. [PubMed: 10213691]

36. Karakiewicz PI, Suardi N, Jeldres C, et al. Neoadjuvant sutent induction therapy may effectivelydown-stage renal cell carcinoma atrial thrombi. Eur Urol 2008;53:845–8. [PubMed: 18053636]

37. Kibel A, Iliopoulos O, DeCaprio JA, et al. Binding of the von Hippel-Lindau tumor suppressorprotein to Elongin B and C. Science 1995;269:1444–6. [PubMed: 7660130]

38. Latif F, Tory K, Gnarra JR, et al. Identification of the von Hippel-Lindau disease tumor suppressorgene. Science 1993;260:1317–20. [PubMed: 8493574]



NIH


NIH


NIH


39. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renalcell cancer. Proc Natl Acad Sci U S A 2001;98:3387–2. [PubMed: 11248088]

40. Linehan WM. Targeting VEGF receptors in kidney cancer. Lancet Oncol 2007;8:956–7. [PubMed:17976606]

41. Linehan, WM.; Bates, SE.; Yang, JC. Cancer of the Kidney. In: DeVita, SE.; Hellman, S.;Rosenberg, SA., editors. Cancer: Principles and Practice of Oncology. 7th. Philadelphia:Lippincott Williams & Wilkins; 2005. p. 1139-1168.

42. Linehan WM, Pinto PA, Srinivasan R, et al. Identification of the genes for kidney cancer:opportunity for disease-specific targeted therapeutics. Clin Cancer Res 2007;13:671s–9s.[PubMed: 17255292]

43. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol2003;170:2163–72. [PubMed: 14634372]

44. Margulis V, Matin SF, Tannir N, et al. Surgical morbidity associated with administration oftargeted molecular therapies before cytoreductive nephrectomy or resection of locally recurrentrenal cell carcinoma. J Urol 2008;180:94–8. [PubMed: 18485389]

45. Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targetshypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271–5. [PubMed:10353251]

46. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinaseinhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors:determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327–37. [PubMed: 12538485]

47. Merino MJ, Torres-Cabala CA, Zbar B, et al. Hereditary Leiomyomatosis and Renal CellCarcinoma Syndrome (HLRCC); Clinical, Histopathological and Molecular Features of the FirstAmerican Families Described. Mod Pathol 2003;16:739.

48. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: adouble-blind, randomised, placebo-controlled phase III trial. Lancet. 2008

49. Motzer RJ, Hudes G, Wilding G, et al. Phase I trial of sunitinib malate plus interferon-alpha forpatients with metastatic renal cell carcinoma. Clin Genitourin Cancer 2009;7:28–33. [PubMed:19213665]

50. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cellcarcinoma. N Engl J Med 2007;356:115–24. [PubMed: 17215529]

51. Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paragangliomasyndromes associated with SDHB and SDHD gene mutations. JAMA 2004;292:943–51. [PubMed:15328326]

52. Nickerson ML, Jaeger E, Shi Y, et al. Improved identification of von Hippel-Lindau genealterations in clear cell renal tumors. Clin Cancer Res 2008;14:4726–34. [PubMed: 18676741]

53. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lungwall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.Cancer Cell 2002;2:157–64. [PubMed: 12204536]

54. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct bindingto the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000;2:423–7. [PubMed:10878807]

55. Ohh M, Takagi Y, Aso T, et al. Synthetic peptides define critical contacts between elongin C,elongin B, and the von Hippel-Lindau protein. J Clin Invest 1999;104:1583–91. [PubMed:10587522]

56. Ornstein DK, Lubensky IA, Venzon D, et al. Prevalence of microscopic tumors in normalappearing renal parenchyma of patients with hereditary papillary renal cancer. J Urol2000;163:431–3. [PubMed: 10647647]

57. Patel PH, Senico PL, Curiel RE, et al. Phase I study combining treatment with temsirolimus andsunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer2009;7:24–7. [PubMed: 19213664]



NIH


NIH


NIH


58. Pause A, Lee S, Worrell RA, et al. The von Hippel-Lindau tumor-suppressor gene product forms astable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad SciU S A 1997;94:2156–61. [PubMed: 9122164]

59. Pavlovich CP, Walther MM, Eyler RA, et al. Renal tumors in the Birt-Hogg-Dube syndrome. Am JSurg Pathol 2002;26:1542–52. [PubMed: 12459621]

60. Pfaffenroth EC, Linehan WM. Genetic basis for kidney cancer: opportunity for disease-specificapproaches to therapy. Expert Opin Biol Ther 2008;8:779–90. [PubMed: 18476789]

61. Ricketts C, Woodward ER, Killick P, et al. Germline SDHB mutations and familial renal cellcarcinoma. J Natl Cancer Inst 2008;100:1260–2. [PubMed: 18728283]

62. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007

63. Rogers CG, Metwalli A, Blatt AM, et al. Robotic partial nephrectomy for renal hilar tumors: amulti-institutional analysis. J Urol 2008;180:2353–6. [PubMed: 18930263]

64. Rogers CG, Singh A, Blatt AM, et al. Robotic partial nephrectomy for complex renal tumors:surgical technique. Eur Urol 2008;53:514–21. [PubMed: 17961910]

65. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domainof the MET proto-oncogene in papillary renal carcinomas. Nature Genetics 1997;16:68–73.[PubMed: 9140397]

66. Schmidt L, Junker K, Nakaigawa N, et al. Novel mutations of the MET proto-oncogene inpapillary renal carcinomas. Oncogene 1999;18:2343–50. [PubMed: 10327054]

67. Schmidt L, Junker K, Weirich G, et al. Two North American families with hereditary papillaryrenal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res1998;58:1719–22. [PubMed: 9563489]

68. Schmidt LS, Nickerson ML, Warren MB, et al. Germline BHD-mutation spectrum and phenotypeanalysis of a large cohort of families with Birt-Hogg-Dube syndrome. Am J Hum Genet2005;76:1023–33. [PubMed: 15852235]

69. Seyam RM, Bissada NK, Kattan SA, et al. Changing trends in presentation, diagnosis andmanagement of renal angiomyolipoma: comparison of sporadic and tuberous sclerosis complex-associated forms. Urol 2008;72:1077–82. [PubMed: 18805573]

70. Shuch B, Riggs SB, LaRochelle JC, et al. Neoadjuvant targeted therapy and advanced kidneycancer: observations and implications for a new treatment paradigm. BJU Int 2008;102:692–6.[PubMed: 18410444]

71. Srinivasan R, Choueiri TK, Vaishampayan U, et al. A phase II study of the dual MET/VEGFR2inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC). Journal of ClinicalOncology 2008;26(May 20 Suppl):5103.

72. Srirangalingam U, Walker L, Khoo B, et al. Clinical manifestations of familial paraganglioma andphaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. ClinEndocrinol (Oxf) 2008;69:587–96. [PubMed: 18419787]

73. Stebbins CE, Kaelin WG Jr, Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex:implications for VHL tumor suppressor function. Science 1999;284:455–61. [PubMed: 10205047]

74. Steffens MG, Boerman OC, Oosterwijk-Wakka JC, et al. Targeting of renal cell carcinoma withiodine-131-labeled chimeric monoclonal antibody G250. J Clin Oncol 1997;15:1529–37.[PubMed: 9193349]

75. Stolle C, Glenn GM, Zbar B, et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998;12:417–23. [PubMed: 9829911]

76. Sudarshan S, Sourbier C, Kong HS, et al. Fumarate hydratase deficiency in renal cancer inducesglycolytic addiction and HIF-1{alpha} stabilization by glucose-dependent generation of reactiveoxygen species. Mol Cell Biol. 2009

77. Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity toinhibitors of mTOR in kidney cancer. Nat Med 2006;12:122–7. [PubMed: 16341243]

78. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantlyinherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet2002;30:406–10. [PubMed: 11865300]



NIH


NIH


NIH


79. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditaryleiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003;73:95–106. [PubMed: 12772087]

80. Toro JR, Pautler SE, Stewart L, et al. Lung Cysts, Spontaneous Pneumothrorax and GeneticAssociations in 89 Families with Birt-Hogg-Dube Syndrome. Am J Respir Crit Care Med2007;175:1044–53. [PubMed: 17322109]

81. Uemura H, Nakagawa Y, Yoshida K, et al. MN/CA IX/G250 as a potential target forimmunotherapy of renal cell carcinomas. Br J Cancer 1999;81:741–6. [PubMed: 10574265]

82. van d V, Meijerink MR, van den Eertwegh AJ, et al. Sunitinib for treatment of advanced renal cellcancer: primary tumor response. Clin Cancer Res 2008;14:2431–6. [PubMed: 18413834]

83. Vanharanta S, Buchta M, McWhinney SR, et al. Early-onset renal cell carcinoma as a novelextraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet2004;74:153–9. [PubMed: 14685938]

84. Vocke CD, Yang Y, Pavlovich CP, et al. High Frequency of Somatic Frameshift BHD GeneMutations in Birt-Hogg-Dube-Associated Renal Tumors. J Natl Cancer Inst 2005;97:931–5.[PubMed: 15956655]

85. Wagner JR, Walther MM, Linehan WM, et al. Interleukin-2 based immunotherapy for metastaticrenal cell carcinoma with the kidney in place. J Urol 1999;162:43–5. [PubMed: 10379736]

86. Walther MM, Alexander RB, Weiss GI, et al. Cytoreductive surgery prior to interleukin-2 basedtherapy in patients with metastatic renal cell carcinoma. Urol 1993;42:250–8. [PubMed: 8379024]

87. Walther MM, Choyke PL, Glenn G, et al. Renal cancer in families with hereditary renal cancer:prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol1999;161:1475–9. [PubMed: 10210376]

88. Walther MM, Choyke PL, Weiss G, et al. Parenchymal sparing surgery in patients with hereditaryrenal cell carcinoma. J Urol 1995;153:913–6. [PubMed: 7853573]

89. Walther MM, Lubensky IA, Venzon D, et al. Prevalence of microscopic lesions in grossly normalrenal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinomaand no renal disease: clinical implications. J Urol 1995;154:2010–4. [PubMed: 7500446]

90. Wei MH, Toure O, Glenn GM, et al. Novel mutations in FH and expansion of the spectrum ofphenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J MedGenet 2006;43:18–27. [PubMed: 15937070]

91. Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitorthat targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther2008;7:3129–40. [PubMed: 18852116]

92. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascularendothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34.[PubMed: 12890841]

93. Zbar B, Alvord WG, Glenn GM, et al. Risk of renal and colonic neoplasms and spontaneouspneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev2002;11:393–400. [PubMed: 11927500]

94. Zbar B, Tory K, Merino MJ, et al. Hereditary papillary renal cell carcinoma. J Urol 1994;151:561–6. [PubMed: 8308957]



NIH


NIH


NIH


Figure 1. Targeting the VHL gene pathway in clear cell kidney cancerThe VHL protein makes a complex with other proteins and targets hypoxia inducible factorfor ubiquitin-mediated degradation. This is an oxygen-sensitive process; when the oxygenlevel is normoxic, the VHL complex targets HIF and degrades it. When there is hypoxia,HIF is not degraded and this causes the transcription of a number of genes known to beimportant in cancer, such as vascular endothelial growth factor (VEGF), platelet derivedgrowth factor (PDGF) and transforming growth factor α (TGF-α). Knowledge of the VHL/HIF pathway provides the foundation for the development of novel therapeutic approachesto the treatment of patients with advanced kidney cancer. Five FDA approved agents,sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab are currently used intreatment of patients with advanced clear cell kidney cancer.(42) (Adapted from Pfaffenroth,et al.(60))



NIH


NIH


NIH


Figure 2. Targeting the MET gene pathway in type 1 papillary kidney cancerHereditary papillary renal carcinoma (HPRC) is a hereditary cancer syndrome in whichaffected individuals are at risk for the development of bilateral, multifocal type 1 papillarykidney cancer.(94) The gene for HPRC was found to be MET, the cell surface receptor forthe ligand, hepatocyte growth factor. Activating mutations in the tyrosine kinase domain ofMET are found in the germline of HPRC patients and in a subset of tumors from patientswith sporadic type 1 papillary kidney cancer.(65,66) In a multicenter Phase II trial, the dualMET/VEGFR2 kinase inhibitor, GSK'089, has shown activity in patients with papillaryRCC, including those with MET mutation.(71) (Adapted from Linehan et al.(43))



NIH


NIH


NIH


Figure 3. Kidney cancer is fundamentally a metabolic disorderThe kidney cancer genes, VHL, MET, BHD, TSC1, TSC2, fumarate hydratase and succinatedehydrogenase, have in common that they are involved in energy, nutrient, iron and oxygensensing. Targeting the metabolic defects in kidney cancer provides the potential for thedevelopment of more durable and effective forms of therapy for patients with this disorder.



NIH


NIH


NIH


NIH


NIH


NIH



Table 1

Targeting the Kidney Cancer Genes

Gene Histology Disease Agent/Approach

VHL Clear Cell von Hippel-Lindau (VHL) Clear Cell RCC Sunitinib(50)

Sorafenib(14)

Bevacuzimab(92)

Temsirolimus(27)

Temsirolimus(27)

Everolimus(48)

Axinitinib(62)

MET Type 1 Papillary Hereditary Papillary Renal Cell Carcinoma (HPRCC) GSK'089(71)

BHD Chromophobe Hybrid Oncocytic Birt-Hogg-Dubé (BHD) Rapamycin(1)

FH Type 2 Papillary Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) Targeting VEGF(29)

TSC1/2 Angiomyolipoma Tuberous Sclerosis (TSC) Sirolimus(3)


Molecular Diagnosis and Therapy of Kidney Cancer*

Documents