Hereditary Papillary Renal Carcinoma Research Articles

Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.

Renal cell carcinoma (RCC) comprises various histologically distinct subtypes, each characterized by specific genetic alterations, necessitating individualized management and treatment strategies for each subtype. An exhaustive search of the PubMed database was conducted without any filters or restrictions. Inclusion criteria encompassed original English articles focusing on molecular mechanisms of kidney cancer. On the other hand, all non-original articles and articles published in any language other than English were excluded. Hereditary kidney cancer represents 5-8% of all kidney cancer cases and is associated with syndromes such as von Hippel-Lindau syndrome, Birt-Hogg-Dubè syndrome, succinate dehydrogenase-deficient renal cell cancer syndrome, tuberous sclerosis complex, hereditary papillary renal cell carcinoma, fumarate hydratase deficiency syndrome, BAP1 tumor predisposition syndrome, and other uncommon hereditary cancer syndromes. These conditions are characterized by distinct genetic mutations and related extra-renal symptoms. The majority of renal cell carcinoma predispositions stem from loss-of-function mutations in tumor suppressor genes. These mutations promote malignant advancement through the somatic inactivation of the remaining allele. This review aims to elucidate the main molecular mechanisms underlying the pathophysiology of major syndromes associated with renal cell carcinoma. By providing a comprehensive overview, it aims to facilitate early diagnosis and to highlight the principal therapeutic options available.

Multiple and hereditary renal tumors: a review for radiologists

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2–4% of "sporadic" multifocality and 5–8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended.Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition.The concept of "non-hereditary" familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

Hereditary cancer syndromes with increased risk of renal cancer

Renal cancer (RC) is one of the three most common diseases in oncologic urology. Its accurate diagnosis and prognosis remain difficult and important problems. Some cases of RC are associated with hereditary cancer syndromes and are caused by germline mutations. This review describes monogenic forms of hereditary RC (von Hippel–Lindau syndrome, Birt–Hogg– Dubé syndrome, hereditary leiomyomatosis and renal cell cancer, hereditary papillary renal carcinoma, BAP1 tumor predisposition syndrome) and diseases with several candidate genes (SDH-mutated tumors, tuberous sclerosis complex). Additionally, the review discusses the increased risk of RC in patients with frequent hereditary cancer syndromes predisposing to the development of a wide range of tumor types: Lynch and Li-Fraumeni syndromes. RC in combination with other carcinomas can develop in patients carrying pathogenic mutations in the candidate genes of different hereditary cancer syndromes – multi-locus inherited neoplasia allele syndrome (MINAS) – which is especially important due to the growing role of high-throughput sequencing in practical oncologic genetics. Additionally, guidelines on modern laboratory genetic diagnostics and active surveillance are presented for each syndrome.

Tumores renales múltiples y hereditarios. Revisión por y para radiólogos

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2-4% of “sporadic” multifocality and 5-8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended.Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition.The concept of “non-hereditary” familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

Hereditary renal tumor syndromes.

Kidney tumors may develop in association with hereditary tumor syndromes. The clinical presentation of these disorders is various, and in some cases, the renal tumor is the first manifestation of the syndrome. Thus, pathologists need to be aware of the gross and histological signs that may suggest the possibility of a tumor syndrome. In this paper, we summarize and illustrate the characteristics of kidney tumors, genetic background along with the extrarenal manifestations in the following diseases: Von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome, Birt-Hogg-Dubé syndrome, tuberous sclerosis, hereditary paraganglioma and pheochromocytoma syndrome, and inherited BAP1 tumor syndrome. At the end of the manuscript, we discuss the tumor syndromes with increased risk of Wilms tumors. Such patients require a holistic approach and multidisciplinary care. Our work aims to make those involved in the diagnosis and treatment of kidney tumors aware of these rare diseases that require life-long surveillance. Orv Hetil. 2023; 164(10): 363-375.

Tumorigenesis Mechanisms Found in Hereditary Renal Cell Carcinoma: A Review.

Renal cell carcinoma is a heterogenous cancer composed of an increasing number of unique subtypes each with their own cellular and tumor behavior. The study of hereditary renal cell carcinoma, which composes just 5% of all types of tumor cases, has allowed for the elucidation of subtype-specific tumorigenesis mechanisms that can also be applied to their sporadic counterparts. This review will focus on the major forms of hereditary renal cell carcinoma and the genetic alterations contributing to their tumorigenesis, including von Hippel Lindau syndrome, Hereditary Papillary Renal Cell Carcinoma, Succinate Dehydrogenase-Deficient Renal Cell Carcinoma, Hereditary Leiomyomatosis and Renal Cell Carcinoma, BRCA Associated Protein 1 Tumor Predisposition Syndrome, Tuberous Sclerosis, Birt-Hogg-Dubé Syndrome and Translocation RCC. The mechanisms for tumorigenesis described in this review are beginning to be exploited via the utilization of novel targets to treat renal cell carcinoma in a subtype-specific fashion.

Novel germline MET pathogenic variants in French patients with papillary renal cell carcinomas type I.

Hereditary papillary renal cell carcinoma (HPRC) is a rare inherited renal cancer syndrome characterized by bilateral and multifocal papillary type 1 renal tumors (PRCC1). Activating germline pathogenic variants of theMET gene were identified in HPRC families. We reviewed the medical and molecular records of a large French series of 158 patients screened for MET oncogenic variants. MET pathogenic and likely pathogenic variants rate was 12.4% with 40.6% among patients with familial PRCC1 and 5% among patients with sporadic PRCC1. The phenotype in cases with MET pathogenic and likely pathogenic variants was characteristic: PRCC1 tumors were mainly bilateral (84.3%) and multifocal (87.5%). Histologically, six out of seven patients with MET pathogenic variant harbored biphasic squamoid alveolar PRCC. Genetic screening identified one novel pathogenic variant MET c.3389T>C, p.(Leu1130Ser) and three novel likely pathogenic variants: MET c.3257A>T, p.(His1086Leu); MET c.3305T>C, p.(Ile1102Thr) and MET c.3373T>G, p.(Cys1125Gly). Functional assay confirmed their oncogenic effect as they induced an abnormal focus formation. The genotype-phenotype correlation between MET pathogenic variants and PRCC1 presentation should encourage to widen the screening, especially toward nonfamilial PRCC1. This precise phenotype also constitutes a strong argument for the classification of novel missense variants within the tyrosine kinase domain when functional assays are not accessible.

Clear cell and papillary renal cell carcinomas in hereditary papillary renal cell carcinoma (HPRCC) syndrome: a case report

BackgroundHereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, distinctive histological features of RCC are described according to the familial renal cell carcinoma syndrome. To date, no clear cell RCC has been reported in HPRCC syndrome.Case presentationWe describe the case of a 51-year-old man with a germline MET mutation detected on peripheral blood testing, and no germline VHL mutation, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed 7 years after the initial diagnosis corresponding to a clear cell RCC metastasis. By immunohistochemistry, clear cell tumors showed focal cytokeratin 7, moderate racemase, and diffuse and membranous CAIX expression, while papillary tumors expressed strong diffuse cytokeratin 7 and racemase without CAIX positivity. Using FISH, VHL deletion was observed in one of the clear cell tumors, and the metastatic clear cell tumor presented a trisomy of chromosomes 7 and 17. These last genomic alterations are usually detected in papillary RCC, highlighting the potential link between both histological subtypes of tumors and the HPRCC syndrome.ConclusionsThe pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study.

Characterization of genetically defined sporadic and hereditary type 1 papillary renal cell carcinoma cell lines.

Renal cell carcinoma (RCC) is not a single disease but is made up of several different histologically defined subtypes that are associated with distinct genetic alterations which require subtype specific management and treatment. Papillary renal cell carcinoma (pRCC) is the second most common subtype after conventional/clear cell RCC (ccRCC), representing ~20% of cases, and is subcategorized into type 1 and type 2 pRCC. It is important for preclinical studies to have cell lines that accurately represent each specific RCC subtype. This study characterizes seven cell lines derived from both primary and metastatic sites of type 1 pRCC, including the first cell line derived from a hereditary papillary renal carcinoma (HPRC)‐associated tumor. Complete or partial gain of chromosome 7 was observed in all cell lines and other common gains of chromosomes 16, 17, or 20 were seen in several cell lines. Activating mutations of MET were present in three cell lines that all demonstrated increased MET phosphorylation in response to HGF and abrogation of MET phosphorylation in response to MET inhibitors. CDKN2A loss due to mutation or gene deletion, associated with poor outcomes in type 1 pRCC patients, was observed in all cell line models. Six cell lines formed tumor xenografts in athymic nude mice and thus provide in vivo models of type 1 pRCC. These type 1 pRCC cell lines provide a comprehensive representation of the genetic alterations associated with pRCC that will give insight into the biology of this disease and be ideal preclinical models for therapeutic studies.

Abstract 4719: Novel germline variants in hereditary renal cell carcinoma genes elucidated by whole genome sequencing

Abstract Whole genome sequencing (WGS) may be utilized to reveal novel germline variants in renal cell carcinoma (RCC) syndrome genes that cannot be characterized by conventional methods. Patients who present with clinical manifestations of von Hippel-Lindau (VHL), Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC), or Hereditary Papillary Renal Carcinoma (HPRC) are routinely evaluated for germline mutations in the VHL, FH (fumarate hydratase), or MET gene, respectively, by genetic testing. Rarely, either a negative result or an unusual finding is reported. For one patient who exhibited multiple clinical manifestations of VHL in the kidneys, pancreas, cerebellum and epididymis but no germline mutation, karyotype analysis revealed that the patient possessed a germline translocation between chromosomes 1 and 3. Two patients with family history of papillary type 1 RCC but no point mutation in MET were determined to have novel germline duplications in all or part of the MET gene. Finally, seven patients with clinical manifestations of HLRCC including cutaneous and uterine leiomyomas and/or family history of RCC, had negative genetic testing. Paired-end WGS was performed on the DNA derived from peripheral blood leucocytes from these patients. WGS for the patient with VHL manifestations revealed that the breakpoint between chromosomes 1 and 3 falls directly within intron 2 of the VHL gene, leading to a novel disruption of VHL in the germline. Sanger sequencing was performed to determine the exact breakpoints on both chromosomes. We believe this to be the first report of a germline chromosomal translocation resulting in VHL syndrome Likewise, both MET duplications were sequenced across the exact breakpoints, revealing a tandem duplication of 601,339 bp including the entire MET gene in one patient, and a tandem duplication of 101,464 bp including exons 5 through 21 in the other patient. As MET is an oncogene, we theorize that these duplications result in increased expression levels. Finally, 4 of 7 patients with clinical manifestations of HLRCC, including a family of three affected members, were found to possess a novel intronic A to G variant in intron 9 of FH that has not been reported in any human genome databases. This variant introduces a cryptic splice acceptor site and thus adds an extra exon of 57 bp to the transcript, resulting in a premature stop codon and thus a truncated protein of 474 amino acids. A cutaneous leiomyoma from one patient demonstrates loss of heterozygosity, substantiating loss of FH function. In conclusion, germline whole genome sequencing should be considered for patients who exhibit clinical manifestations of a hereditary RCC disease syndrome but for whom no sequence variants are detected by standard genetic testing, in order to improve the detection rate of novel germline variants. Citation Format: Cathy D. Vocke, Christopher J. Ricketts, Daniel R. Crooks, Martin Lang, Laura S. Schmidt, Mayank Tandon, Bao Tran, Christina Fitzsimmons, Pedro J. Batista, Mark W. Ball, W. Marston Linehan. Novel germline variants in hereditary renal cell carcinoma genes elucidated by whole genome sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4719.

Fumarate Hydratase-Deficient Renal Cell Carcinoma

A woman in her thirties presented with a 7.5 cm renal mass and a 12 cm pelvic mass. She underwent a hysterectomy which showed a large uterine leiomyoma, and a nephrectomy which showed a papillary renal cell carcinoma. A representative image of the papillary renal cell carcinoma is depicted. Based on the clinical presentation, what syndrome should this patient be screened for and what ancillary tools can be used to confirm the diagnosis?a.Hereditary papillary renal cell carcinoma; next generation sequencing for the MET proto-oncogeneb.Carney-Stratakis syndrome associated renal cancer; immunohistochemistry and next generation sequencing for the succinate dehydrogenase genesc.Hereditary leiomyomatosis and renal cell carcinoma associated renal cancer; immunohistochemistry and next generation sequencing for the fumarate hydratase gened.Tuberous sclerosis complex associated renal cancer; genetic testing for germline alterations of TSC1/TSC2 genes Answer: c. Hereditary leiomyomatosis and renal cell carcinoma associated renal cancer; immunohistochemistry and next generation sequencing for the fumarate hydratase gene Fumarate hydratase-deficient renal carcinomas can occur both in the germline and somatic setting. Germline pathogenic alterations of the FH (fumerate hydratase) gene are associated with hereditary leiomyomatosis and renal cell carcinoma associated renal cancer. These patients present with clinically aggressive renal tumors as well as uterine and cutaneous leiomyomas. Immunohistochemistry can be used to screen for these tumors (frequent loss of FH protein and high levels of covalent modifications of cysteine residues [S-(2-succino)-cysteine (2SC)] secondary to aberrant protein succination.1Gupta S. Swanson A.A. Chen Y.B. et al.Incidence of succinate dehydrogenase and fumarate hydratase-deficient renal cell carcinoma based on immunohistochemical screening with SDHA/SDHB and FH/2SC.Hum Pathol. 2019; 91: 114-122Crossref PubMed Scopus (18) Google Scholar Next generation sequencing can be used to confirm pathogenic alterations of the FH gene. Hereditary papillary renal cell carcinoma occurs secondary to germline alterations of the MET proto-oncogene. Carney-Stratakis syndrome involves germline alterations of the succinate dehydrogenase genes and is typically not associated with renal cancer. Tuberous sclerosis occurs secondary to germline alterations of TSC1/TSC2 genes and is typically not associated with uterine leiomyomas.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

IPSC-Derived Embryoid Bodies as Models of c-Met-Mutated Hereditary Papillary Renal Cell Carcinoma

Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis, as a driving oncogenic event is present in germline. Currently, there are no satisfactory models to study these malignancies. We report the generation of IPSC from the somatic cells of a patient with hereditary c-met-mutated papillary renal cell carcinoma (PRCC). From these cells we have generated spontaneous aggregates organizing in structures which expressed kidney markers such as PODXL and Six2. These structures expressed PRCC markers both in vitro and in vivo in NSG mice. Gene-expression profiling showed striking molecular similarities with signatures found in a large cohort of PRCC tumor samples. This analysis, applied to primary cancers with and without c-met mutation, showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated embryoid bodies transcriptome. These data therefore represent the first proof of concept of “hereditary renal cancer in a dish” model using c-met-mutated iPSC-derived embryoid bodies, opening new perspectives for discovery of novel predictive progression markers and for drug-screening for future precision-medicine strategies.

PD07-04 GROWTH RATES OF GENETICALLY-DEFINED RENAL TUMORS: IMPLICATIONS FOR ACTIVE SURVEILLANCE AND INTERVENTION

INTRODUCTION AND OBJECTIVES:Genetically-defined renal cell carcinomas (RCC), including those associated with von Hippel-Lindau (VHL; clear cell RCC, VHL gene), Hereditary Papillary Renal Carcinoma ...

PD51-01 MANAGEMENT OF GENETICALLY DEFINED RENAL TUMORS UTILIZING SIZE-BASED RISK STRATIFICATION: LONG-TERM RESULTS

You have accessJournal of UrologyKidney Cancer: Localized: Active Surveillance1 Apr 2018PD51-01 MANAGEMENT OF GENETICALLY DEFINED RENAL TUMORS UTILIZING SIZE-BASED RISK STRATIFICATION: LONG-TERM RESULTS Mark Ball, Julie An, James Peteron, Maria Merino, Ramaprasad Srinivasan, Adam Metwalli, and W. Marston Linehan Mark BallMark Ball More articles by this author , Julie AnJulie An More articles by this author , James PeteronJames Peteron More articles by this author , Maria MerinoMaria Merino More articles by this author , Ramaprasad SrinivasanRamaprasad Srinivasan More articles by this author , Adam MetwalliAdam Metwalli More articles by this author , and W. Marston LinehanW. Marston Linehan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2341AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Genetically defined renal cell carcinomas, including those associated with von Hippel-Lindau (VHL; clear cell RCC, VHL gene), Hereditary Papillary Renal Carcinoma (HPRC, Type 1 Papillary RCC, MET gene) Birt-Hogg-Dubé (BHD, chromophobe RCC, FLCN gene), Hereditary Leiomyomatosis and Renal Cell Carcinomas (HLRCC; Type 2 Papillary RCC, Fumarate Hydratase gene) and Succinate Dehydrogenase RCC (SDHRCC, eosinophilic RCC, SDHB gene) are managed at our institution based on genotype. While metastasis may develop with small (< 3 cm) HLRCC or SDHRCC renal tumors, based on early observations of low metastatic potential of small lesions renal lesions in VHL, HPRC and BHD, these patients have been managed with active surveillance until the largest tumor reaches 3 cm, at which time surgical resection of ipsilateral tumors is recommended. The present study was performed in order to evaluate the oncologic efficacy of the 3 cm size threshold with in a cohort of VHL, HPRC and BHD patients with long-term follow-up. METHODS Patients managed on prospective National Cancer Institute Institutional Review-approved protocols with VHL-, HPRC- and BHD-associated solid renal masses were identified. The diameter of the largest solid tumor, the length of follow-up, the presence of metastatic disease was evaluated. The proportion of patients who developed metastatic disease at size thresholds beyond 3 cm was assessed in 1 cm increments. Metastasis-free survival (MFS) was defined as the interval from initial screening to development of metastatic disease. RESULTS A total of 634 patients with genetically defined RCC were identified, including 440 with VHL-, 43 with HPRC- and 151 with BHD-associated renal tumors. While metastatic disease was found to have developed in 42 patients (10.1%) with VHL-, 6 (14%) with HPRC-, and 8 (5.3%) with BHD-associated RCC, to date, no patient who underwent surgical resection when the largest tumor was < 3 cm has yet developed metastatic disease. Table 1 lists the proportion of patients who developed metastases by size of their largest tumor. MFS for VHL patients whose renal tumors were resected when they reached 3 cm threshold was significantly longer compared to those who were not (p=0.007). The 5, 10 and 20-year MFS for patients whose tumors had not been resected when they reached the 3 cm threshold was 95.7%, 91.1%, and 69.5%, respectively. CONCLUSIONS In a cohort of 634 patients with VHL-, HPRC- and BHD-associated RCC adherence to the 3 cm guideline was associated with superior MFS compared to those who were not. In addition, these findings may have broad applicability for the management of non-hereditary genetically defined renal tumors. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e975 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Mark Ball More articles by this author Julie An More articles by this author James Peteron More articles by this author Maria Merino More articles by this author Ramaprasad Srinivasan More articles by this author Adam Metwalli More articles by this author W. Marston Linehan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract CN04-03: Targeting the metabolic basis of kidney cancer

Abstract Renal cell carcinoma (RCC) affects nearly 300,000 people worldwide each year and is responsible for over 100,000 deaths each year. RCC is not a single disease; it is made up of a number of different types of cancer, with different histologies and clinical courses, responding differently to therapy and caused by different genes. There are currently 17 genes known to cause RCC, 14 of which are associated with inherited forms of the disease. Study of the RCC gene pathways has shown that RCC is fundamentally a metabolic disease. Much of what is known about the genetic basis of RCC has been learned from studying RCC-predisposition families. von Hippel-Lindau (VHL) is a hereditary cancer syndrome in which affected individuals are at risk for the development of tumors in a number of organs, including the kidneys. Patients affected with VHL are at risk for the development of bilateral, multifocal, clear cell renal cell carcinoma. Genetic linkage analysis in VHL families was performed to identify the VHL gene on the short arm of chromosome 3. VHL gene mutation that segregates with the disease is identified in 100% of VHL families. VHL gene mutation or methylation is also found in a high percentage of tumors from patients with sporadic, nonfamilial clear cell RCC. The product of the VHL gene, pVHL, has been found to form a complex with elongin C, elongin B, Cul2, and RBX1 to target the hypoxia-induced factors, HIF1/2, for oxygen-dependent ubiquitin-mediated degradation. Although 9 targeted therapeutic agents have been approved by the FDA for the treatment of patients with advanced RCC, many patients eventually progress and may succumb to this disease. High-grade, high-stage, low-survival clear cell RCC has been shown to be characterized by a pattern consistent with aerobic glycolysis, reduced oxidative phosphorylation, and a dependence on the pentose phosphate shunt. Clinical trials targeting the metabolic basis of clear cell RCC, including targeting HIF2 transcription, are currently under way. Hereditary papillary renal cell carcinoma (HPRC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal type 1 papillary RCC. HPRC is characterized by germline mutation of the MET proto-oncogene. MET gene alteration or amplification is found in a high percentage of tumors from patients with nonhereditary, sporadic Type 1 papillary renal cell carcinoma (PRCC). Clinical trials are currently under way targeting the MET pathway in patients with Type 1 PRCC. Birt-Hogg-Dubé is an inherited form of chromophobe RCC (ChRCC) in which affected individuals are at risk for the development of bilateral multifocal chromophobe and hybrid oncocytic RCC. Genetic linkage analysis identified the FLCN as the Birt-Hogg-Dubé gene. The product of the FLCN gene, folliculin, forms a complex with the FLCN binding proteins, FNIP1/2, and the gamma subunit of AMPK. Inactivation of the FLCN has been shown to result in activation of mTORC1/mTORC2. A clinical trial is currently being conducted to evaluate the effect of targeting the mTORC1 pathway in patients with Birt-Hogg-Dubé-associated renal tumors. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and an aggressive form of Type 2 PRCC. HLRCC is characterized by mutation of the gene for the Krebs cycle enzyme, fumarate hydratase (FH). HLRCC-associated type 2 PRCC has been shown to be characterized by a Warburg shift to aerobic glycolysis with decreased oxidative phosphorylation and a glutamine-dependent reductive carboxylation. Clinical trials are currently under way evaluating the effect of agents targeting the FH pathway in patients with HLRCC-associated RCC. SDH-RCC is an inherited from of renal cell carcinoma that occurs in families with germline mutation of succinate dehydrogenase (SDH) B,C, or D genes. Similar to FH-deficient RCC, SDH-RCC is characterized by a metabolic shift to aerobic glycolysis, significantly impaired oxidative phosphorylation (consistent with complex 2 dysfunction), and a glutamine-dependent reductive carboxylation. SDH-RCC renal tumors are malignant and have a propensity to spread when they are small. Understanding the metabolic basis of renal cell carcinoma has the potential to provide the foundation for the development of more effective forms of therapy for patients with these cancers.

Renal cell cancers: unveiling the hereditary ones and saving lives-a tailored diagnostic approach.

The prevalence of RCC in Europe is 2-3% and increasing every year. Hereditary predisposition is found in 5-8% of all RCC cases. Hereditary syndromes associated with RCC include: Von Hippel-Lindau, hereditary papillary renal cell carcinoma, Birt-Hogg-Dube', hereditary leiomyomatosis, succinate dehydrogenase's deficiency, tuberous sclerosis complex and Cowden's syndrome. These syndromes are related to specific genetic mutations. So far the European Association of Urology and American Urological Association have not established guidelines for referral of patients with RCC for germline mutation screening. The scope of this article is to review which clinical manifestations should direct clinicians' thinking towards hereditary kidney carcinomas and therefore suggest which patients could benefit from genetic testing.

MET in human cancer: germline and somatic mutations.

Since the initial discovery of missense MET mutations in hereditary papillary renal carcinoma (HPRC), activating MET mutations have been identified in a diverse range of human cancers. MET mutations have been identified in several functional domains including the kinase, juxtamembrane, and Sema domains. Studies of these mutations have been invaluable for our understanding of the tumor initiating activity of MET, receptor tyrosine kinase (RTK) recycling and regulation, and mechanisms of resistance to kinase inhibition. These studies also demonstrate that mutationally activated MET plays a significant role in a wide range of cancers and RTKs can promote tumor progression through diverse mechanisms. This review will cover the various MET mutations that have been identified, their mechanism of action, and the significant role that mutationally-activated MET plays in tumor initiation, progression, and therapeutic resistance.

Pharmacodynamic Response of the MET/HGF Receptor to Small-Molecule Tyrosine Kinase Inhibitors Examined with Validated, Fit-for-Clinic Immunoassays.

Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect. Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models. By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET:MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation. These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. Clin Cancer Res; 22(14); 3683-94. ©2016 AACR.

Inherited renal carcinomas

Hereditary forms of kidney carcinoma account for 5-8% of all malignant kidney neoplasms. The renal tumors are often multiple and bilateral and occur at an earlier age. Each of the hereditary kidney carcinoma syndromes is associated with specific gene mutations as well as a specific histologic type of kidney carcinoma. The presence of associated extrarenal manifestations may suggest a hereditary kidney cancer syndrome. Radiology is most commonly used to screen and manage patients with hereditary kidney cancer syndromes. This manuscript reviews the clinical and imaging findings of well-defined inherited kidney cancer syndromes including von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary papillary renal carcinoma syndrome, hereditary leiomyomatosis and RCC syndrome, tuberous sclerosis complex, and Lynch syndrome.

MP73-15 METASTATIC PAPILLARY RENAL CANCER: DOES HEREDITARY ORIGIN IMPACT SURVIVAL?

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging I1 Apr 2016MP73-15 METASTATIC PAPILLARY RENAL CANCER: DOES HEREDITARY ORIGIN IMPACT SURVIVAL? Abhinav Sidana, Meet Kadakia, Julia Friend, Akhil Muthigi, Louis Krane, Geri Hawks, Martha Ninos, W Martson Linehan, and Ramaprasad Srinivasan Abhinav SidanaAbhinav Sidana More articles by this author , Meet KadakiaMeet Kadakia More articles by this author , Julia FriendJulia Friend More articles by this author , Akhil MuthigiAkhil Muthigi More articles by this author , Louis KraneLouis Krane More articles by this author , Geri HawksGeri Hawks More articles by this author , Martha NinosMartha Ninos More articles by this author , W Martson LinehanW Martson Linehan More articles by this author , and Ramaprasad SrinivasanRamaprasad Srinivasan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1670AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hereditary forms of renal cancer tend to have a younger age of onset but there is little data to address the impact of early onset on survival compared to patients with sporadic forms of metastatic papillary renal cell cancer (pRCC). The primary objective of our study is to compare overall survival between hereditary and sporadic forms of metastatic pRCC. The secondary objective is to identify predictors for overall survival in hereditary forms of metastatic pRCC. METHODS Retrospective evaluation of the medical records of patients with metastatic pRCC seen at the Urologic Oncology Branch, National Cancer Institute (2000-2014) was undertaken. Patient demographics, tumor characteristics and outcomes were studied. Overall survival of the groups was estimated by Kaplan-Meier survival analysis. Univariate Cox proportional hazard regression analysis was done to identify predictors of overall survival. RESULTS One hundred and six patients with metastatic pRCC were identified, of whom 53 (50.0%) had a hereditary variant (49 with Hereditary Leiomyomatosis and Renal Cell Cancer, 3 with Hereditary Papillary Renal Cell Carcinoma, and 1 with Birt-Hogg-Dube). In our cohort, metastatic hereditary pRCC were more likely to be papillary type 2 than sporadic forms (p<0.001). Hereditary pRCC patients presented (mean age 40.1 vs 54.7 years, p<0.001) and developed metastasis (mean age 42.0 vs 57.3 years, p<0.001) at a younger age than sporadic pRCC patients. No difference in tumor staging at presentation was found between the two groups. While mean time from primary diagnosis to metastasis was shorter in hereditary group (32.7 vs 45.7 months, p=0.446), the difference was not statistically significant. There was no difference in estimated median overall survival after development of metastasis (40.8 vs 35.1 months, p=0.801) between the two groups. Corrected calcium greater than 10 (p=0.012), elevated lactate dehydrogenase (p=0.010), neutrophil-lymphocyte ratio >5 (p=0.013) and platelet-lymphocyte ratio >210 (p=0.001) at the time of initiation of systemic therapy predicted worse overall survival in hereditary metastatic pRCC. CONCLUSIONS Hereditary pRCC patients presented and developed metastasis at a younger age than those with sporadic forms but the overall survival after the development of metastasis was comparable between two groups. Several traditional prognostic factors of survival identified in sporadic RCC also appear to predict survival in hereditary forms. To our knowledge, this is the first report detailing survival and prognostic factors in patients with hereditary metastatic pRCC. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e966 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Abhinav Sidana More articles by this author Meet Kadakia More articles by this author Julia Friend More articles by this author Akhil Muthigi More articles by this author Louis Krane More articles by this author Geri Hawks More articles by this author Martha Ninos More articles by this author W Martson Linehan More articles by this author Ramaprasad Srinivasan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...