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Familial Renal Cancer: Molecular Genetics and Surgical Management

Familial Renal Cancer: Molecular Genetics and Surgical Management Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 658767, 11 pages doi:10.1155/2011/658767 Review Article Familial Renal Cancer: Molecular Genetics and Surgical Management 1 2 1 Glen W. Barrisford, Eric A. Singer, Inger L. Rosner, 2 2, 3 W. Marston Linehan, and Gennady Bratslavsky Department of Urology, National Naval Medical Center, Bethesda, MD 20889, USA Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 1-5940, Bethesda, MD 20892, USA Department of Urology, Upstate Medical University, SUNY, Syracuse, NY 13210, USA Correspondence should be addressed to Gennady Bratslavsky, bratslag@upstate.edu Received 1 March 2011; Accepted 31 May 2011 Academic Editor: Bernardo Garicochea Copyright © 2011 Glen W. Barrisford et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dube(BHD) are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer. 1. Introduction is often curative, up to 30% of patients will present with systemic disease, while an additional 30% will develop Renal cell carcinoma (RCC) has a global impact with approx- metastatic lesions in followup after an initial presentation of imately 111,100 new cases and 43,000 deaths from the disease organ confined disease [8]. Treatment of systemic disease has among men in developed countries in 2008 alone [1]. In often been challenging due to the fact that RCC represents 2010, RCC ranked as the seventh and eighth most common a heterogeneous spectrum of diverse entities. Each subtype malignancy in men and women in the United States, respec- of renal malignancy is known to possess unique clinical tively, and 58,240 new cases and 13,040 deaths were expected characteristics, genetic alterations, and has varied responses [2]. Americans face a diagnosis of renal malignancy at a rate to therapy. The dominant malignant subtypes recognized by of approximately 1 in 67 over the course of their lifetime [3]. the Heidelberg classification system include clear cell (con- The increased availability and use of cross-sectional imaging ventional) (70–80%), papillary (chromophile) (10–15%), as well as other imaging modalities tends to diagnose renal chromophobe (3–5%), and collecting duct (1%) tumors [9]. tumors at earlier stages and often as incidental findings. Papillary tumors are further stratified into type 1 (5%) and However, despite the increased and advanced detection, the type 2 (10%) based upon genetic and histologic variation associated mortality rate has not declined [4]. Unexpectedly, [10–12] (Figure 1). the increased incidence of RCC cannot be entirely explained RCC can exist as both hereditary and sporadic entities. by the more widespread use of imaging modalities [5]. Sporadic RCC typically presents as a solitary lesion and will Surgical resection has historically been the mainstay of occur more commonly in patients in the sixth decade and therapy as RCC is known to be resistant to radiation and beyond. Conversely, hereditary forms of kidney cancer often traditional chemotherapy [6, 7]. Although surgical resection present with multifocal, bilateral tumors and may present 2 International Journal of Surgical Oncology (a) (b) (c) (d) Figure 1: Histopathology of the most common malignant renal neoplasms. (a) Clear cell; (b) papillary type 1; (c) papillary type 2; and (d) chromophobe. (From Linehan et al. [10], with permission.) in far younger patients [13]. Many cases of hereditary renal the forms of FRC with a known genetic alteration is that they malignancy go unrecognized or unreported as this spectrum are metabolic in nature, as the genes involved with FRC are of diseasesisnot well understood [14]. Moderate estimates associated with abnormalities in oxygen, iron, glucose, and place hereditary disease forms at 3–5% of the overall number energy sensing [18]. The identification of genetic aberrations of diagnoses [15, 16]. Liberally defined, familial renal cancer associated with familial forms of kidney cancer has led to the (FRC) is noted to exist when more than one member of elucidation of a number of interrelated metabolic pathways. a family presents with a single malignancy or collection of As a result, a number of targeted molecular therapies have tumors [16]. developed over the past half decade [19]. This has altered the The identification of FRC is critical in that it allows for management of advanced and systemic RCC and provided the early screening of families, vigilant followup for those additional approaches to cytokine-based therapies for the affected, appropriate and measured interventions when systemic therapy of clear cell tumors [20, 21]. The treatment needed, and the reduction of disease-related morbidity of choice for nonclear cell histologies is presently less well and mortality. When a patient’s family history is positive defined [22]. Understanding the genetic abnormalities and for kidney cancer, or a patient with one or more of the the pathways leading to the tumorigenesis of FRC provided physical/radiographic findings outlined in Table 1 is found the opportunity for the development of novel forms of to have a renal mass, further investigation and referral to therapies targeting these cancer gene pathways (Table 1). a genetic counselor are often reasonable. The American Society of Clinical Oncology’s recently published guidelines 2. Von Hippel-Lindau on genetic testing for cancer susceptibility concisely identify and explain many of the ethical issues associated with germ Von Hippel-Lindau (VHL) is a hereditary renal cancer syn- line analysis [17]. drome associated with clear cell renal tumors. The inheri- FRC is a heterogeneous disease comprised of a spectrum tance pattern is autosomal dominant, and the incidence is 1 of varied histologic subtypes. The fundamental link among in 36,000 live births [10, 24, 25]. The disease can manifest International Journal of Surgical Oncology 3 Table 1: Familial renal cancer syndromes. Mendelian Syndrome Phenotype Renal cancer manifestation Gene Chromosome Inheritance in Man (MIM) number Renal tumors, adrenal pheochromocytomas, retinal angiomas, central nervous Von system hemangioblastomas, Hippel-Lindau pancreatic cysts and Clear cell renal cell carcinoma VHL 3p25 193300 (VHL) neuroendocrine tumors, endolymphatic sac tumors, epididymal and broad ligament cystadenomas Hereditary Papillary renal cell carcinoma papillary renal Bilateral, multifocal renal tumors MET 7q31 164860 type 1 carcinoma (HPRC) Hereditary leiomyomatosis Skin and uterine leiomyomas, Papillary renal cell carcinoma and renal cell FH 1q42-43 605839 renal tumors type 2 carcinoma (HLRCC) Hybrid oncocytic, Cutaneous fibrofolliculomas, Birt-Hogg-Dube´ chromophobe, and clear cell lung cysts, spontaneous FLCN 17p11 135150 (BHD) renal cell carcinoma; pneumothorax, renal tumors oncocytoma clinically with renal tumors, adrenal pheochromocytomas, a higher incidence of RCC and greater extent of involvement retinal angiomas, central nervous system hemangioblas- among various organ systems as compared to those with tomas, pancreatic cysts, neuroendocrine tumors, endolym- complete deletions [33, 36, 37]. phatic sac tumors, and cystadenomas of the epididymis and VHL gene function has been rigorously studied. It is a broad ligament. Each of these tumors is known to be highly relatively small gene encoding 854 nucleotides on three exons vascular. Improvement in treatment for central nervous and encodes the VHL protein [29]. The VHL protein (pVHL) system tumors has had the effect of elevating metastatic forms a complex with elongin B, elongin C, Cul 2, and Rbx1 renal cell carcinoma to the leading cause of mortality among [38–40]. This complex targets the hypoxia-inducible factors these patients. Renal tumors appear in 35–45% of affected (HIF), HIF-1α and HIF-2α, and is essential for ubiquitin- individuals, can be solid or cystic, and are of clear cell mediated degradation [41, 42]. The transcription products histology [26]. Patients can develop up to 600 microscopic of HIF-1α and HIF-2α are known to regulate a number of tumors and over 1100 cysts per kidney [13, 24]. downstream genes that are involved in tumorigenesis. The VHL-associated tumors were noted to have a consistent main examples of these genes are vascular endothelial growth loss of the short arm of chromosome 3 [27]. Genetic linkage factor (VEGF), platelet derived growth factor (PDGF), epi- studies in patients with hereditary and sporadic renal cancer dermal growth factor receptor (EGFR), transforming growth led to the identification of the VHL gene on the short arm factor (TGF-α), and glucose transporter (GLUT-1). During of chromosome 3 (3p26-25) [28, 29]. This gene is a tumor conditions of normal tissue oxygen levels, the VHL complex suppressor, and the loss of a single normal allele was observed binds to HIF initiating ubiquitin-mediated degradation. in the VHL gene in kidney cancer tissue samples [30]. This However, during conditions of low tissue oxygen levels, observation suggested that there existed an inherited gene at the VHL complex does not degrade HIF which results in this location. This germline alteration was observed in VHL- a surge of HIF levels and an upregulation of transcrip- associated kidney cancer and is found in nearly 100% of tion of HIF-dependent genes [13, 43]. In the instance of VHL families [31]. Somatic VHL alterations are observed in clear cell RCC, a VHL gene alteration changes the alpha a high percentage of sporadic clear cell renal tumors but are domain (which binds elongin C/B and Cul 2) or the beta absent in papillary, chromophobe, or collecting duct tumors subunit (which targets HIF for breakdown). These changes [32]. There are currently more than 300 known alterations result in a buildup of HIF and consequently an increased available for testing that involve the VHL gene [33, 34]. The expression of the downstream genes (Figure 2). The pVHL location and type of the VHL gene alteration can result in protein causes an effect similar to hypoxia and can activate the expression of different phenotypes. Penetrance is widely pathways for cellular proliferation and neovascularization. varied, and certain traits (pheochromocytomas) tend to be This effect takes place under normoxic conditions and clustered in certain families while absent in others [35]. has been termed “pseudohypoxia” [12, 44]. Many of the Patients with partial germline deletions are noted to have current therapeutic management approaches for clear cell 4 International Journal of Surgical Oncology E2 CUL 2 Rbx1 ElonginB VHL complex ElonginC disrupted Mutant VHL protein β domain α domain HIF-1α and HIF-2α accumulation VEGF Glut 1 TGF-α G G Angiogenesis Glucose transport Autocrine growth stimulation (a) E2 CUL 2 Rbx1 Elongin B VHL complex Elongin C disrupted HIF-1α and HIF-2α Mutant VHL protein accumulation β domain α domain HIF-1α and HIF-2α VEGF EGFR accumulation Anti-VEGF/EGFR Small molecule kinase inhibitor inhibitor VEGF Autocrine growth TGF-α Angiogenesis PDGF stimulation (b) (c) Figure 2: The VHL complex targets HIF-1α and HIF-2α for ubiquitin-mediated degradation. In clear cell RCC, an alteration in the VHL gene in the α or β domain disrupts HIF degradation. HIF overaccumulates leading to increased transcription of downstream genes. (a) VHL alteration; (b) VHL/HIF pathway molecular targeting; and (c) VHL/HIF downstream molecular targeting. (From Linehan and Zbar [23], with permission.) RCC are based upon the targeting of the receptors for HIF- 3. Hereditary Papillary Renal Carcinoma regulated genes [45]. The agents currently approved by the Hereditary papillary renal carcinoma (HPRC) is an inherited US Food and Drug Administration to treat metastatic clear renal cancer syndrome in which affected individuals are at cell RCC via the targeting of VHL transcription products include sunitinib, sorafenib, bevacizumab plus interferon-α, risk of developing multifocal bilateral type 1 papillary renal carcinoma. It follows an autosomal dominant inheritance pazopanib, temsirolimus, and everolimus [19]. These agents form the foundation for systemic therapy in a disease that pattern with very high penetrance, meaning that there is a high likelihood of a person developing papillary RCC by has been resilient in the face of cytotoxic chemotherapy and radiotherapy [6, 7, 21]. Despite the great progress in the age 80 [46]. Affected individuals are generally at risk of arena of targeted therapy, the bulk of the work has been developing tumors in the sixth through eighth decades [47]. in clear cell histology, and treatment for other histologic The only involved organ in HPRC is the kidney. The tumors subtypes is presently less well established [22]. are typically well differentiated but are malignant and can International Journal of Surgical Oncology 5 Met receptor For example, foretinib is an oral tyrosine kinase receptor inhibitor that targets c-MET and VEGFR2 that has been studied in a phase II multicenter trial [58]. Activating mutation 4. Hereditary Leiomyomatosis and Proliferation- Renal Cell Cancer papillary kidney cancer Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary renal cancer syndrome that was initially reported in 2001 by Launonen et al. [60]. Individuals affected with this syndrome are at risk of developing papillary type 2 renal tumors as well as cutaneous and uterine leiomyomas. These Figure 3: Alterations in the intracellular tyrosine kinase domain of aggressive renal lesions can be mistaken for collecting duct the MET proto-oncogene are found in patients with HPRC. These RCC tumors [61]. Although papillary type 2 lesions can mutations result in the activation of the MET pathway. (From Line- occur in a sporadic fashion, those associated with HLRCC han et al. [10], with permission.) tend to occur as unilateral solitary lesions that are very aggressive, prone to metastasis, and lethal if afforded the opportunity to progress [62, 63]. The gene responsible for metastasize. Initial descriptions of the disease describe it HLRCC was identified by Tomlinson et al. on chromosome as “late onset”, occurring in the later decades of life [46, 1 (1q42-44) and is known as fumarate hydratase (FH). This 48]. However, within the last decade, an early onset form gene functions as a tumor suppressor, and both alleles are of HPRC has been identified [49]. Renal tumors in these inactivated in tumor tissue [64]. The FH gene is inherited in patients are often diagnosed incidentally [50]. an autosomal dominant fashion with high penetrance. Computed tomography (CT) and magnetic resonance Fumarate hydratase is a critical enzyme in aerobic me- imaging (MRI) are the imaging modalities of choice when tabolism. Its role in the Krebs cycle is the conversion of evaluating patients with HPRC as they demonstrate greater fumarate to malate. Alteration to FH upregulates HIF and sensitivity when compared to renal ultrasound [51]. How- creates a pseudohypoxic environment that is similarly seen in ever, these lesions are typically small and hypovascular with VHL. When FH is inactivated, fumarate levels build up and poor enhancement on CT imaging. HPRC lesions can easily competitively inhibit HIF prolyl hydroxylase (HPH). HPH be mistaken for renal cysts, and a high index of suspicion is a key enzymatic regulator of intracellular HIF levels [65]. is needed. In these cases, ultrasound is a useful adjunct When HPH is inactivated, HIF levels rise and transcription to differentiate cystic from solid lesions, although the solid of the downstream genes occurs (Figure 4). There is presently lesions may be isoechoic to normal renal parenchyma. no known sporadic counterpart to HLRCC renal malignancy HPRC-affected families were evaluated and found to be and no evidence to support a relationship between the FH devoid of abnormalities on chromosome 3. However, within mutation and tumorigenesis in nonfamilial cancers. How- the first few years of the identification of the syndrome, ever, in 93% of HLRCC families (52/56), germline alterations research yielded the gene responsible for HPRC on chro- were identified in the FH gene [66]. mosome 7q31 [46, 48]. The germline alteration in HPRC Potential areas of systematic therapy for HLRCC will activates a proto-oncogene. The missense mutations in the likely be designed to prevent increased HIF levels or target tyrosine kinase domain of the MET proto-oncogene at 7q31 the transcription products of VHL-independent HIF accu- are responsible for the constitutive activation of the MET mulation, such as VEGF and TGF-α/EGFR. One attempt to protein. The MET transmembrane protein is located at a block the downstream affects of FH inactivation is through hepatocyte growth factor receptor site, and a tyrosine kinase the use of erlotinib, an oral EGFR tyrosine kinase inhibitor domain is located intracellularly [52]. Hepatocyte growth (TKI). A multicenter phase II trial of this agent in patients factor activates MET tyrosine phosphorylation which in with locally advanced and metastatic papillary RCC reported turn induces proliferation and differentiation of epithelial an overall RECIST response rate of 11% with an additional and endothelial cells, cell branching, and invasion [13, 53] 24 patients (53%) experiencing stable disease [67]. (Figure 3). MET alterations in somatic cells have been iden- Combination therapy with an mTOR inhibitor or VEGF tified in a division of patients with sporadic papillary type 1 pathway antagonist may potentiate the single agent activity renal cancer [54]. Changes in the MET gene involve ligand- of erlotinib. A phase II trial of erlotinib (EGFR TKI) in com- independent activation of the intracytoplasmic tyrosine bination with bevacizumab (monoclonal antibody against kinase domain leading to activation of the hepatocyte growth VEGF) is currently underway and is one of the trials designed factor (HGF)/MET pathway resulting in tumor formation to evaluate this strategy [68]. [55, 56]. HPRC families retain germline changes in the MET gene with nonrandom duplication of chromosome 7 with the 5. Birt-Hogg-Dube´ altered MET allele [57]. Molecular targeting aimed to inhibit HGF, and the sub- Birt-Hogg-Dube´ (BHD) is a hereditary renal cancer syn- sequent downstream pathways could be a potential therapy drome that is associated with chromophobe renal tumors. of papillary type 1 RCC in patients with HPRC [12]. The inheritance pattern is autosomal dominant, and affected 6 International Journal of Surgical Oncology Normoxia HLRCC HIF TCA cycle FH HPH HIF HPH Fumarate HIF VHL OH complex HIF Proteosome Transcription PDGF VEGF GLUT-1 TGF-α Ubiquitin-mediated degradation Paracrine Angiogenesis Glucose Autocrine growth transport growth stimulation stimulation Figure 4: In a normoxic environment, HIF is hydroxylated by HPH allowing the VHL complex to initiate ubiquitin-mediated breakdown in the proteosome. In HLRCC, FH alteration results in a buildup of fumarate. Fumarate competitively inhibits HPH allowing a rise in HIF levels and subsequent transcription of downstream genes. (From Pfaffenroth and Linehan [59], with permission.) individuals develop cutaneous fibrofolliculomas, pulmonary and reduce renal manifestations of BHD in FLCN knockout cysts, spontaneous pneumothoraces, and renal tumors [70]. mice [78]. This represents a potential therapeutic role for In identified genetic carriers, renal tumors were observed mTOR inhibitors in patients affected by BHD-related renal in 14–34%, spontaneous pneumothoracies in 23%, and tumors. At present, the role of mTOR pathways in sporadic pulmonary cysts in 83% [14]. The majority of the renal chromophobe tumors is under investigation (Figure 5). tumors are of chromophobe histology (33%), hybrid tumors (50%), and oncocytomas (5%). Multifocal oncocytosis is 6. Surgical Management seen in the surrounding renal parenchyma in 50% of the affected individuals. In addition, clear cell RCC is seen in Patients with FRC are likely to develop multifocal, bilateral, patients with BHD [71]. and recurrent renal tumors. In managing these patients, two The BHD gene, folliculin (FLCN), was localized to chro- goals are paramount: prevention of metastatic disease and mosome 17 and was subsequently identified at 17p11.2 preservation of renal function. At the National Cancer Insti- [72, 73]. FLCN is altered as a result of insertions, deletions, tute, the first goal has been achieved largely through diligent or nonsense mutations [74]. FLCN deficiency activates the surveillance serial cross-sectional imaging and observation mammalian target of rapamycin (mTOR) pathway [75]. The until the dominant lesion achieves a size of 3 cm [79]. When a FLCN gene has the traits of a tumor suppressor and requires lesion becomes 3 cm, surgical intervention is recommended. two mutations with the second hit inactivating the gene [76]. In patients adhering to this “3 cm rule”, none developed FLCN forms a complex with folliculin-interacting pro- metastatic disease with more than 10 years followup [80]. teins (FNIP1 and FNIP2). These components intern bind to It should be noted, however, that the 3 cm rule was initially AMP-activated protein kinase (AMPK). AMPK acts to sense developed in the VHL population and later expanded to cellular energy and assists in the regulation of the mTOR include HPRC and BHD patients. Patients with HLRCC and activity level [75, 77]. In tumors that are noted to have FLCN any evidence of solid tumor are offered surgical extirpation alterations in both alleles, mTOR activation (mTORC1 and given the highly aggressive nature of their disease. Active mTORC2) has been observed [69]. Rapamycin inhibits the surveillance is not recommended for HLRCC patients with mTOR pathway and has been noted to prolong survival renal tumors. The second goal of renal preservation has X International Journal of Surgical Oncology 7 FLCN + Growth factor Putative negative feedback loop to P13K-AKT-mTOR P13K PTEN mTORC2 Akt FoxO GSK3 TSC2 BAD Energy LKB1 TSC1 and nutrient sensing AMPK mTORC1 S6K FNIP1 FNIP2 FLCN Translational control (a) FLCN − Growth factor P13K PTEN mTORC2 Akt GSK3 TSC2 FoxO BAD Energy LKB1 TSC1 and nutrient sensing AMPK mTORC1 S6K FNIP1 FNIP2 Translational control FLCN (b) Figure 5: FLCN pathway. (a) FLCN is the gene associated with BHD. Normal FCLN protein complexes with FNIP1, FNIP2, and AMPK. This complex is phosphorylated by a rapamycin-sensitive kinase (mTORC1). (b) When FLCN is altered, it fails to complex and allows activation of AKT, mTORC1, and mTORC2. (From Hasumi et al. [69], with permission.) been achieved with a committed approach to nephron- a complicated management dilemma, and this particular sparing surgery (NSS) using open, laparoscopic, and robotic situation is occurring with greater frequency as a result of approaches [81–83]. the increased use of nephron sparing surgery [82]. In the The development of locally recurrent renal tumors is rare setting of local recurrence, management options include in sporadic disease but more common in patients with FRC, observation, initial or repeat ablation, repeat or salvage although it is difficult to distinguish recurrent disease from partial nephrectomy, radical nephrectomy, or systemic ther- adjacent de novo tumor in the majority of cases. Disease apy. Each management option presents a unique array of recurrence in the ipsilateral renal unit has been described risks and benefits. The majority of renal units can be at the same site or elsewhere in the kidney after both salvaged in the face of disease recurrence. However, it comes partial nephrectomy and ablative therapy (cryoablation or at the cost of increased perioperative complication rates radio frequency ablation) [84–86]. This scenario presents [82]. 8 International Journal of Surgical Oncology Reoperation for locally recurrent disease is often associ- Acknowledgment ated with a difficult dissection due to disruption of normal This paper was supported by the Intramural Research Pro- anatomic tissue planes as well as perinephric scarring. Com- gram of the NIH, National Cancer Institute, Center for Can- plication rates increase with the number and complexity cer Research. of repeated interventions on the ipsilateral kidney. Greater operative times, blood loss, and perioperative complications Disclosure are typically observed [87]. The overall major complication rate approaches 20% with repeat partial nephrectomy [88], The views expressed in this paper are those of the authors whereas complication rates in surgically na¨ıve patients range and do not necessarily reflect the official policy or position of from 11% to 13% [89, 90]. The most common complication the Department of the Navy, Army, Department of Defense, among reoperative patients is urinary leak. However, this was nor the US Government. noted to resolve in all patients [88]. Other complications The authors certify that all individuals who qualify as include bowel injury, renovascular injury, and, rarely, loss authors have been listed; that each has participated in the conception and design of this work, the analysis of data of a renal unit or death. Although the risks associated with (when applicable), the writing of the document, and the repeated surgical intervention on the same renal unit are approval of the submission of this version; that the document significant, they are offset by the benefits of avoiding the represents valid work; that if we used information derived morbidity and mortality associated with renal replacement from another source, they obtained all necessary approvals therapy. While the treatment algorithm offers many branch to use it and made the appropriate acknowledgments in points, the complexity and increased risk associated with the document; that each takes public responsibility for these procedures demand referral to an experienced sur- it. Nothing in the presentation implies any Federal/DOD/ geon at a medical center that can provide comprehensive DON/DOA endorsement. care. In cases of metastatic disease, surgical treatment options References alone are typically inadequate. 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Familial Renal Cancer: Molecular Genetics and Surgical Management

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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 658767, 11 pages doi:10.1155/2011/658767 Review Article Familial Renal Cancer: Molecular Genetics and Surgical Management 1 2 1 Glen W. Barrisford, Eric A. Singer, Inger L. Rosner, 2 2, 3 W. Marston Linehan, and Gennady Bratslavsky Department of Urology, National Naval Medical Center, Bethesda, MD 20889, USA Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 1-5940, Bethesda, MD 20892, USA Department of Urology, Upstate Medical University, SUNY, Syracuse, NY 13210, USA Correspondence should be addressed to Gennady Bratslavsky, bratslag@upstate.edu Received 1 March 2011; Accepted 31 May 2011 Academic Editor: Bernardo Garicochea Copyright © 2011 Glen W. Barrisford et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dube(BHD) are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer. 1. Introduction is often curative, up to 30% of patients will present with systemic disease, while an additional 30% will develop Renal cell carcinoma (RCC) has a global impact with approx- metastatic lesions in followup after an initial presentation of imately 111,100 new cases and 43,000 deaths from the disease organ confined disease [8]. Treatment of systemic disease has among men in developed countries in 2008 alone [1]. In often been challenging due to the fact that RCC represents 2010, RCC ranked as the seventh and eighth most common a heterogeneous spectrum of diverse entities. Each subtype malignancy in men and women in the United States, respec- of renal malignancy is known to possess unique clinical tively, and 58,240 new cases and 13,040 deaths were expected characteristics, genetic alterations, and has varied responses [2]. Americans face a diagnosis of renal malignancy at a rate to therapy. The dominant malignant subtypes recognized by of approximately 1 in 67 over the course of their lifetime [3]. the Heidelberg classification system include clear cell (con- The increased availability and use of cross-sectional imaging ventional) (70–80%), papillary (chromophile) (10–15%), as well as other imaging modalities tends to diagnose renal chromophobe (3–5%), and collecting duct (1%) tumors [9]. tumors at earlier stages and often as incidental findings. Papillary tumors are further stratified into type 1 (5%) and However, despite the increased and advanced detection, the type 2 (10%) based upon genetic and histologic variation associated mortality rate has not declined [4]. Unexpectedly, [10–12] (Figure 1). the increased incidence of RCC cannot be entirely explained RCC can exist as both hereditary and sporadic entities. by the more widespread use of imaging modalities [5]. Sporadic RCC typically presents as a solitary lesion and will Surgical resection has historically been the mainstay of occur more commonly in patients in the sixth decade and therapy as RCC is known to be resistant to radiation and beyond. Conversely, hereditary forms of kidney cancer often traditional chemotherapy [6, 7]. Although surgical resection present with multifocal, bilateral tumors and may present 2 International Journal of Surgical Oncology (a) (b) (c) (d) Figure 1: Histopathology of the most common malignant renal neoplasms. (a) Clear cell; (b) papillary type 1; (c) papillary type 2; and (d) chromophobe. (From Linehan et al. [10], with permission.) in far younger patients [13]. Many cases of hereditary renal the forms of FRC with a known genetic alteration is that they malignancy go unrecognized or unreported as this spectrum are metabolic in nature, as the genes involved with FRC are of diseasesisnot well understood [14]. Moderate estimates associated with abnormalities in oxygen, iron, glucose, and place hereditary disease forms at 3–5% of the overall number energy sensing [18]. The identification of genetic aberrations of diagnoses [15, 16]. Liberally defined, familial renal cancer associated with familial forms of kidney cancer has led to the (FRC) is noted to exist when more than one member of elucidation of a number of interrelated metabolic pathways. a family presents with a single malignancy or collection of As a result, a number of targeted molecular therapies have tumors [16]. developed over the past half decade [19]. This has altered the The identification of FRC is critical in that it allows for management of advanced and systemic RCC and provided the early screening of families, vigilant followup for those additional approaches to cytokine-based therapies for the affected, appropriate and measured interventions when systemic therapy of clear cell tumors [20, 21]. The treatment needed, and the reduction of disease-related morbidity of choice for nonclear cell histologies is presently less well and mortality. When a patient’s family history is positive defined [22]. Understanding the genetic abnormalities and for kidney cancer, or a patient with one or more of the the pathways leading to the tumorigenesis of FRC provided physical/radiographic findings outlined in Table 1 is found the opportunity for the development of novel forms of to have a renal mass, further investigation and referral to therapies targeting these cancer gene pathways (Table 1). a genetic counselor are often reasonable. The American Society of Clinical Oncology’s recently published guidelines 2. Von Hippel-Lindau on genetic testing for cancer susceptibility concisely identify and explain many of the ethical issues associated with germ Von Hippel-Lindau (VHL) is a hereditary renal cancer syn- line analysis [17]. drome associated with clear cell renal tumors. The inheri- FRC is a heterogeneous disease comprised of a spectrum tance pattern is autosomal dominant, and the incidence is 1 of varied histologic subtypes. The fundamental link among in 36,000 live births [10, 24, 25]. The disease can manifest International Journal of Surgical Oncology 3 Table 1: Familial renal cancer syndromes. Mendelian Syndrome Phenotype Renal cancer manifestation Gene Chromosome Inheritance in Man (MIM) number Renal tumors, adrenal pheochromocytomas, retinal angiomas, central nervous Von system hemangioblastomas, Hippel-Lindau pancreatic cysts and Clear cell renal cell carcinoma VHL 3p25 193300 (VHL) neuroendocrine tumors, endolymphatic sac tumors, epididymal and broad ligament cystadenomas Hereditary Papillary renal cell carcinoma papillary renal Bilateral, multifocal renal tumors MET 7q31 164860 type 1 carcinoma (HPRC) Hereditary leiomyomatosis Skin and uterine leiomyomas, Papillary renal cell carcinoma and renal cell FH 1q42-43 605839 renal tumors type 2 carcinoma (HLRCC) Hybrid oncocytic, Cutaneous fibrofolliculomas, Birt-Hogg-Dube´ chromophobe, and clear cell lung cysts, spontaneous FLCN 17p11 135150 (BHD) renal cell carcinoma; pneumothorax, renal tumors oncocytoma clinically with renal tumors, adrenal pheochromocytomas, a higher incidence of RCC and greater extent of involvement retinal angiomas, central nervous system hemangioblas- among various organ systems as compared to those with tomas, pancreatic cysts, neuroendocrine tumors, endolym- complete deletions [33, 36, 37]. phatic sac tumors, and cystadenomas of the epididymis and VHL gene function has been rigorously studied. It is a broad ligament. Each of these tumors is known to be highly relatively small gene encoding 854 nucleotides on three exons vascular. Improvement in treatment for central nervous and encodes the VHL protein [29]. The VHL protein (pVHL) system tumors has had the effect of elevating metastatic forms a complex with elongin B, elongin C, Cul 2, and Rbx1 renal cell carcinoma to the leading cause of mortality among [38–40]. This complex targets the hypoxia-inducible factors these patients. Renal tumors appear in 35–45% of affected (HIF), HIF-1α and HIF-2α, and is essential for ubiquitin- individuals, can be solid or cystic, and are of clear cell mediated degradation [41, 42]. The transcription products histology [26]. Patients can develop up to 600 microscopic of HIF-1α and HIF-2α are known to regulate a number of tumors and over 1100 cysts per kidney [13, 24]. downstream genes that are involved in tumorigenesis. The VHL-associated tumors were noted to have a consistent main examples of these genes are vascular endothelial growth loss of the short arm of chromosome 3 [27]. Genetic linkage factor (VEGF), platelet derived growth factor (PDGF), epi- studies in patients with hereditary and sporadic renal cancer dermal growth factor receptor (EGFR), transforming growth led to the identification of the VHL gene on the short arm factor (TGF-α), and glucose transporter (GLUT-1). During of chromosome 3 (3p26-25) [28, 29]. This gene is a tumor conditions of normal tissue oxygen levels, the VHL complex suppressor, and the loss of a single normal allele was observed binds to HIF initiating ubiquitin-mediated degradation. in the VHL gene in kidney cancer tissue samples [30]. This However, during conditions of low tissue oxygen levels, observation suggested that there existed an inherited gene at the VHL complex does not degrade HIF which results in this location. This germline alteration was observed in VHL- a surge of HIF levels and an upregulation of transcrip- associated kidney cancer and is found in nearly 100% of tion of HIF-dependent genes [13, 43]. In the instance of VHL families [31]. Somatic VHL alterations are observed in clear cell RCC, a VHL gene alteration changes the alpha a high percentage of sporadic clear cell renal tumors but are domain (which binds elongin C/B and Cul 2) or the beta absent in papillary, chromophobe, or collecting duct tumors subunit (which targets HIF for breakdown). These changes [32]. There are currently more than 300 known alterations result in a buildup of HIF and consequently an increased available for testing that involve the VHL gene [33, 34]. The expression of the downstream genes (Figure 2). The pVHL location and type of the VHL gene alteration can result in protein causes an effect similar to hypoxia and can activate the expression of different phenotypes. Penetrance is widely pathways for cellular proliferation and neovascularization. varied, and certain traits (pheochromocytomas) tend to be This effect takes place under normoxic conditions and clustered in certain families while absent in others [35]. has been termed “pseudohypoxia” [12, 44]. Many of the Patients with partial germline deletions are noted to have current therapeutic management approaches for clear cell 4 International Journal of Surgical Oncology E2 CUL 2 Rbx1 ElonginB VHL complex ElonginC disrupted Mutant VHL protein β domain α domain HIF-1α and HIF-2α accumulation VEGF Glut 1 TGF-α G G Angiogenesis Glucose transport Autocrine growth stimulation (a) E2 CUL 2 Rbx1 Elongin B VHL complex Elongin C disrupted HIF-1α and HIF-2α Mutant VHL protein accumulation β domain α domain HIF-1α and HIF-2α VEGF EGFR accumulation Anti-VEGF/EGFR Small molecule kinase inhibitor inhibitor VEGF Autocrine growth TGF-α Angiogenesis PDGF stimulation (b) (c) Figure 2: The VHL complex targets HIF-1α and HIF-2α for ubiquitin-mediated degradation. In clear cell RCC, an alteration in the VHL gene in the α or β domain disrupts HIF degradation. HIF overaccumulates leading to increased transcription of downstream genes. (a) VHL alteration; (b) VHL/HIF pathway molecular targeting; and (c) VHL/HIF downstream molecular targeting. (From Linehan and Zbar [23], with permission.) RCC are based upon the targeting of the receptors for HIF- 3. Hereditary Papillary Renal Carcinoma regulated genes [45]. The agents currently approved by the Hereditary papillary renal carcinoma (HPRC) is an inherited US Food and Drug Administration to treat metastatic clear renal cancer syndrome in which affected individuals are at cell RCC via the targeting of VHL transcription products include sunitinib, sorafenib, bevacizumab plus interferon-α, risk of developing multifocal bilateral type 1 papillary renal carcinoma. It follows an autosomal dominant inheritance pazopanib, temsirolimus, and everolimus [19]. These agents form the foundation for systemic therapy in a disease that pattern with very high penetrance, meaning that there is a high likelihood of a person developing papillary RCC by has been resilient in the face of cytotoxic chemotherapy and radiotherapy [6, 7, 21]. Despite the great progress in the age 80 [46]. Affected individuals are generally at risk of arena of targeted therapy, the bulk of the work has been developing tumors in the sixth through eighth decades [47]. in clear cell histology, and treatment for other histologic The only involved organ in HPRC is the kidney. The tumors subtypes is presently less well established [22]. are typically well differentiated but are malignant and can International Journal of Surgical Oncology 5 Met receptor For example, foretinib is an oral tyrosine kinase receptor inhibitor that targets c-MET and VEGFR2 that has been studied in a phase II multicenter trial [58]. Activating mutation 4. Hereditary Leiomyomatosis and Proliferation- Renal Cell Cancer papillary kidney cancer Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary renal cancer syndrome that was initially reported in 2001 by Launonen et al. [60]. Individuals affected with this syndrome are at risk of developing papillary type 2 renal tumors as well as cutaneous and uterine leiomyomas. These Figure 3: Alterations in the intracellular tyrosine kinase domain of aggressive renal lesions can be mistaken for collecting duct the MET proto-oncogene are found in patients with HPRC. These RCC tumors [61]. Although papillary type 2 lesions can mutations result in the activation of the MET pathway. (From Line- occur in a sporadic fashion, those associated with HLRCC han et al. [10], with permission.) tend to occur as unilateral solitary lesions that are very aggressive, prone to metastasis, and lethal if afforded the opportunity to progress [62, 63]. The gene responsible for metastasize. Initial descriptions of the disease describe it HLRCC was identified by Tomlinson et al. on chromosome as “late onset”, occurring in the later decades of life [46, 1 (1q42-44) and is known as fumarate hydratase (FH). This 48]. However, within the last decade, an early onset form gene functions as a tumor suppressor, and both alleles are of HPRC has been identified [49]. Renal tumors in these inactivated in tumor tissue [64]. The FH gene is inherited in patients are often diagnosed incidentally [50]. an autosomal dominant fashion with high penetrance. Computed tomography (CT) and magnetic resonance Fumarate hydratase is a critical enzyme in aerobic me- imaging (MRI) are the imaging modalities of choice when tabolism. Its role in the Krebs cycle is the conversion of evaluating patients with HPRC as they demonstrate greater fumarate to malate. Alteration to FH upregulates HIF and sensitivity when compared to renal ultrasound [51]. How- creates a pseudohypoxic environment that is similarly seen in ever, these lesions are typically small and hypovascular with VHL. When FH is inactivated, fumarate levels build up and poor enhancement on CT imaging. HPRC lesions can easily competitively inhibit HIF prolyl hydroxylase (HPH). HPH be mistaken for renal cysts, and a high index of suspicion is a key enzymatic regulator of intracellular HIF levels [65]. is needed. In these cases, ultrasound is a useful adjunct When HPH is inactivated, HIF levels rise and transcription to differentiate cystic from solid lesions, although the solid of the downstream genes occurs (Figure 4). There is presently lesions may be isoechoic to normal renal parenchyma. no known sporadic counterpart to HLRCC renal malignancy HPRC-affected families were evaluated and found to be and no evidence to support a relationship between the FH devoid of abnormalities on chromosome 3. However, within mutation and tumorigenesis in nonfamilial cancers. How- the first few years of the identification of the syndrome, ever, in 93% of HLRCC families (52/56), germline alterations research yielded the gene responsible for HPRC on chro- were identified in the FH gene [66]. mosome 7q31 [46, 48]. The germline alteration in HPRC Potential areas of systematic therapy for HLRCC will activates a proto-oncogene. The missense mutations in the likely be designed to prevent increased HIF levels or target tyrosine kinase domain of the MET proto-oncogene at 7q31 the transcription products of VHL-independent HIF accu- are responsible for the constitutive activation of the MET mulation, such as VEGF and TGF-α/EGFR. One attempt to protein. The MET transmembrane protein is located at a block the downstream affects of FH inactivation is through hepatocyte growth factor receptor site, and a tyrosine kinase the use of erlotinib, an oral EGFR tyrosine kinase inhibitor domain is located intracellularly [52]. Hepatocyte growth (TKI). A multicenter phase II trial of this agent in patients factor activates MET tyrosine phosphorylation which in with locally advanced and metastatic papillary RCC reported turn induces proliferation and differentiation of epithelial an overall RECIST response rate of 11% with an additional and endothelial cells, cell branching, and invasion [13, 53] 24 patients (53%) experiencing stable disease [67]. (Figure 3). MET alterations in somatic cells have been iden- Combination therapy with an mTOR inhibitor or VEGF tified in a division of patients with sporadic papillary type 1 pathway antagonist may potentiate the single agent activity renal cancer [54]. Changes in the MET gene involve ligand- of erlotinib. A phase II trial of erlotinib (EGFR TKI) in com- independent activation of the intracytoplasmic tyrosine bination with bevacizumab (monoclonal antibody against kinase domain leading to activation of the hepatocyte growth VEGF) is currently underway and is one of the trials designed factor (HGF)/MET pathway resulting in tumor formation to evaluate this strategy [68]. [55, 56]. HPRC families retain germline changes in the MET gene with nonrandom duplication of chromosome 7 with the 5. Birt-Hogg-Dube´ altered MET allele [57]. Molecular targeting aimed to inhibit HGF, and the sub- Birt-Hogg-Dube´ (BHD) is a hereditary renal cancer syn- sequent downstream pathways could be a potential therapy drome that is associated with chromophobe renal tumors. of papillary type 1 RCC in patients with HPRC [12]. The inheritance pattern is autosomal dominant, and affected 6 International Journal of Surgical Oncology Normoxia HLRCC HIF TCA cycle FH HPH HIF HPH Fumarate HIF VHL OH complex HIF Proteosome Transcription PDGF VEGF GLUT-1 TGF-α Ubiquitin-mediated degradation Paracrine Angiogenesis Glucose Autocrine growth transport growth stimulation stimulation Figure 4: In a normoxic environment, HIF is hydroxylated by HPH allowing the VHL complex to initiate ubiquitin-mediated breakdown in the proteosome. In HLRCC, FH alteration results in a buildup of fumarate. Fumarate competitively inhibits HPH allowing a rise in HIF levels and subsequent transcription of downstream genes. (From Pfaffenroth and Linehan [59], with permission.) individuals develop cutaneous fibrofolliculomas, pulmonary and reduce renal manifestations of BHD in FLCN knockout cysts, spontaneous pneumothoraces, and renal tumors [70]. mice [78]. This represents a potential therapeutic role for In identified genetic carriers, renal tumors were observed mTOR inhibitors in patients affected by BHD-related renal in 14–34%, spontaneous pneumothoracies in 23%, and tumors. At present, the role of mTOR pathways in sporadic pulmonary cysts in 83% [14]. The majority of the renal chromophobe tumors is under investigation (Figure 5). tumors are of chromophobe histology (33%), hybrid tumors (50%), and oncocytomas (5%). Multifocal oncocytosis is 6. Surgical Management seen in the surrounding renal parenchyma in 50% of the affected individuals. In addition, clear cell RCC is seen in Patients with FRC are likely to develop multifocal, bilateral, patients with BHD [71]. and recurrent renal tumors. In managing these patients, two The BHD gene, folliculin (FLCN), was localized to chro- goals are paramount: prevention of metastatic disease and mosome 17 and was subsequently identified at 17p11.2 preservation of renal function. At the National Cancer Insti- [72, 73]. FLCN is altered as a result of insertions, deletions, tute, the first goal has been achieved largely through diligent or nonsense mutations [74]. FLCN deficiency activates the surveillance serial cross-sectional imaging and observation mammalian target of rapamycin (mTOR) pathway [75]. The until the dominant lesion achieves a size of 3 cm [79]. When a FLCN gene has the traits of a tumor suppressor and requires lesion becomes 3 cm, surgical intervention is recommended. two mutations with the second hit inactivating the gene [76]. In patients adhering to this “3 cm rule”, none developed FLCN forms a complex with folliculin-interacting pro- metastatic disease with more than 10 years followup [80]. teins (FNIP1 and FNIP2). These components intern bind to It should be noted, however, that the 3 cm rule was initially AMP-activated protein kinase (AMPK). AMPK acts to sense developed in the VHL population and later expanded to cellular energy and assists in the regulation of the mTOR include HPRC and BHD patients. Patients with HLRCC and activity level [75, 77]. In tumors that are noted to have FLCN any evidence of solid tumor are offered surgical extirpation alterations in both alleles, mTOR activation (mTORC1 and given the highly aggressive nature of their disease. Active mTORC2) has been observed [69]. Rapamycin inhibits the surveillance is not recommended for HLRCC patients with mTOR pathway and has been noted to prolong survival renal tumors. The second goal of renal preservation has X International Journal of Surgical Oncology 7 FLCN + Growth factor Putative negative feedback loop to P13K-AKT-mTOR P13K PTEN mTORC2 Akt FoxO GSK3 TSC2 BAD Energy LKB1 TSC1 and nutrient sensing AMPK mTORC1 S6K FNIP1 FNIP2 FLCN Translational control (a) FLCN − Growth factor P13K PTEN mTORC2 Akt GSK3 TSC2 FoxO BAD Energy LKB1 TSC1 and nutrient sensing AMPK mTORC1 S6K FNIP1 FNIP2 Translational control FLCN (b) Figure 5: FLCN pathway. (a) FLCN is the gene associated with BHD. Normal FCLN protein complexes with FNIP1, FNIP2, and AMPK. This complex is phosphorylated by a rapamycin-sensitive kinase (mTORC1). (b) When FLCN is altered, it fails to complex and allows activation of AKT, mTORC1, and mTORC2. (From Hasumi et al. [69], with permission.) been achieved with a committed approach to nephron- a complicated management dilemma, and this particular sparing surgery (NSS) using open, laparoscopic, and robotic situation is occurring with greater frequency as a result of approaches [81–83]. the increased use of nephron sparing surgery [82]. In the The development of locally recurrent renal tumors is rare setting of local recurrence, management options include in sporadic disease but more common in patients with FRC, observation, initial or repeat ablation, repeat or salvage although it is difficult to distinguish recurrent disease from partial nephrectomy, radical nephrectomy, or systemic ther- adjacent de novo tumor in the majority of cases. Disease apy. Each management option presents a unique array of recurrence in the ipsilateral renal unit has been described risks and benefits. The majority of renal units can be at the same site or elsewhere in the kidney after both salvaged in the face of disease recurrence. However, it comes partial nephrectomy and ablative therapy (cryoablation or at the cost of increased perioperative complication rates radio frequency ablation) [84–86]. This scenario presents [82]. 8 International Journal of Surgical Oncology Reoperation for locally recurrent disease is often associ- Acknowledgment ated with a difficult dissection due to disruption of normal This paper was supported by the Intramural Research Pro- anatomic tissue planes as well as perinephric scarring. Com- gram of the NIH, National Cancer Institute, Center for Can- plication rates increase with the number and complexity cer Research. of repeated interventions on the ipsilateral kidney. Greater operative times, blood loss, and perioperative complications Disclosure are typically observed [87]. The overall major complication rate approaches 20% with repeat partial nephrectomy [88], The views expressed in this paper are those of the authors whereas complication rates in surgically na¨ıve patients range and do not necessarily reflect the official policy or position of from 11% to 13% [89, 90]. The most common complication the Department of the Navy, Army, Department of Defense, among reoperative patients is urinary leak. However, this was nor the US Government. noted to resolve in all patients [88]. Other complications The authors certify that all individuals who qualify as include bowel injury, renovascular injury, and, rarely, loss authors have been listed; that each has participated in the conception and design of this work, the analysis of data of a renal unit or death. Although the risks associated with (when applicable), the writing of the document, and the repeated surgical intervention on the same renal unit are approval of the submission of this version; that the document significant, they are offset by the benefits of avoiding the represents valid work; that if we used information derived morbidity and mortality associated with renal replacement from another source, they obtained all necessary approvals therapy. While the treatment algorithm offers many branch to use it and made the appropriate acknowledgments in points, the complexity and increased risk associated with the document; that each takes public responsibility for these procedures demand referral to an experienced sur- it. Nothing in the presentation implies any Federal/DOD/ geon at a medical center that can provide comprehensive DON/DOA endorsement. care. In cases of metastatic disease, surgical treatment options References alone are typically inadequate. 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