Hereditary Kidney Cancer 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.

Malignant tumors in tuberous sclerosis complex: a case report and review of the literature

BackgroundTuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disease that arises from TSC1 or TSC2 genetic mutations. These genetic mutations can induce the development of benign tumors in any organ system with significant clinical implications in morbidity and mortality. In rare instances, patients with TSC can have malignant tumors, including renal cell carcinoma (RCC) and pancreatic neuroendocrine tumor (PNET). It is considered a hereditary renal cancer syndrome despite the low incidence of RCC in TSC patients. TSC is typically diagnosed in prenatal and pediatric patients and frequently associated with neurocognitive disorders and seizures, which are often experienced early in life. However, penetrance and expressivity of TSC mutations are highly variable. Herein, we present a case report, with associated literature, to highlight that there exist undiagnosed adult patients with less penetrant features, whose clinical presentation may contain non-classical signs and symptoms, who have pathogenic TSC mutations.Case presentationA 31-year-old female with past medical history of leiomyomas status post myomectomy presented to the emergency department for a hemorrhagic adnexal cyst. Imaging incidentally identified a renal mass suspicious for RCC. Out of concern for hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, the mass was surgically removed and confirmed as RCC. Discussion with medical genetics ascertained a family history of kidney cancer and nephrectomy procedures and a patient history of ungual fibromas on the toes. Genetic testing for hereditary kidney cancer revealed a 5’UTR deletion in the TSC1 gene, leading to a diagnosis of TSC. Following the diagnosis, dermatology found benign skin findings consistent with TSC. About six months after the incidental finding of RCC, a PNET in the pancreatic body/tail was incidentally found on chest CT imaging, which was removed and determined to be a well-differentiated PNET. Later, a brain MRI revealed two small cortical tubers, one in each frontal lobe, that were asymptomatic; the patient’s history and family history did not contain seizures or learning delays. The patient presently shows no evidence of recurrence or metastatic disease, and no additional malignant tumors have been identified.ConclusionsTo our knowledge, this is the first report in the literature of a TSC patient without a history of neurocognitive disorders with RCC and PNET, both independently rare occurrences in TSC. The patient had a strong family history of renal disease, including RCC, and had several other clinical manifestations of TSC, including skin and brain findings. The incidental finding and surgical removal of RCC prompted the genetic evaluation and diagnosis of TSC, leading to a comparably late diagnosis for this patient. Reporting the broad spectrum of disease for TSC, including more malignant phenotypes such as the one seen in our patient, can help healthcare providers better identify patients who need genetic evaluation and additional medical care.

Defining the origin, evolution, and immune composition of SDH-deficient renal cell carcinoma

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is little evidence to guide systemic therapeutic options. We performed genomic profiling of a cohort of tumors through the analysis of whole genomes, transcriptomes, as well as flow cytometry and immunohistochemistry in order to gain a deeper understanding of their molecular biology. We find neutral evolution after early tumor activation with a lack of secondary driver events. We show that these tumors have epithelial derivation, possibly from the macula densa, a specialized paracrine cell of the renal juxtaglomerular apparatus. They subsequently develop into immune excluded tumors. We provide transcriptomic and protein expression evidence of a highly specific tumor marker, PAPPA2. These translational findings have implications for the diagnosis and treatment for this rare tumor subtype.

Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers

SummaryOur understanding of how each hereditary kidney cancer adapts to its tissue microenvironment is incomplete. Here, we present single-cell transcriptomes of 108,342 cells from patient specimens including from six hereditary kidney cancers. The transcriptomes displayed distinct characteristics of the cell of origin and unique tissue microenvironment for each hereditary kidney cancer. Of note, hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated kidney cancer retained some characteristics of proximal tubules, which were completely lost in lymph node metastases and present as an avascular tumor with suppressed T cells and TREM2-high macrophages, leading to immune tolerance. Birt-Hogg-Dubé (BHD)-associated kidney cancer exhibited transcriptomic intratumor heterogeneity (tITH) with increased characteristics of intercalated cells of the collecting duct and upregulation of FOXI1-driven genes, a critical transcription factor for collecting duct differentiation. These findings facilitate our understanding of how hereditary kidney cancers adapt to their tissue microenvironment.

Single-Cell Transcriptomes of Hereditary Kidney Cancers Underscore Genetically Defined Tumor Characteristics and Microenvironment

Single-Cell Transcriptomes of Hereditary Kidney Cancers Underscore Genetically Defined Tumor Characteristics and Microenvironment

Hereditary kidney cancer - easily clarified and diagnosed with ToSCaNA

In recent years great improvements in the diagnosis and differentiation of hereditary syndroms with predisposition for kidney cancer have been achieved. It has been assumed that 5-8% of all kidney cancer have a hereditary origin. In reality, this number will probably be much higher as many genetic aspects of kidney cancer are still not entirely known. Hereditary kidney cancer usually shows two characteristic properties: While the median age of diagnosis of sporadic renal cell carcinoma is 64 years, patients with a hereditary tumor predisposition are about 20 years younger at the time of diagnosis. Additionally, their tumors often occur multifocal/bilateral. Therefore, a special management with extended diagnostics is necessary for these young kidney cancer patients. In literature many reports on hereditary syndromes with kidney cancer predisposition exist. Though, these papers usually put their focus on single syndromes rather than on the aspects of kidney cancer. The goal of this article is to present the practicing urologist with a compact overview of the most important hereditary syndromes with kidney cancer predisposition and by this improve the primary diagnostic and treatment of renal cancer patients and their relatives. We conducted a literature search on the five most important hereditary syndromes with kidney cancer association and summarized the results in a chart. Additionally, we formed the acronym ToSCaNA combining the most important extrarenal manifestations of the syndromes. Based on this data, a diagnostic workflow and treatment path was established. All in all, hereditary kidney cancer is a rare entity, which nonetheless could present as a significant number in high-volume centers. For doctors who scarcely get in contact with these types of tumors, the acronym and workflow could pose a valuable asset for their clinical diagnostic portfolio. An early identification and diagnostic work-up of affected patients and their relatives is crucial for appropriate treatment and surveillance and allows the identification/treatment of additionally affected relatives. In patients with young age of onset and multifocal/bilateral occurrence of kidney cancer, hereditary syndromes should always be considered. The initial suspicion of a hereditary genesis of the cancer can be further evaluated by the acronym ToSCaNA and the presented workflow.

Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement.

Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC. In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.

18Fluorodeoxyglucose-positron emission tomography/computed tomography for differentiation of renal tumors in hereditary kidney cancer syndromes.

To assess differences in FDG-PET/CT uptake among four subtypes of renal tumors: clear cell RCC (ccRCC), papillary type I and II RCC (pRCC), and oncocytoma. This retrospective study investigated 33 patients with 98 hereditary renal tumors. Lesions greater than 1cm and patients with a timeframe of less than 18months between preoperative imaging and surgery were considered. FDG-PET/CT images were independently reviewed by two nuclear medicine physicians, blinded to clinical information. Volumetric lesion SUVmean was measured and used to calculate a target-to-background ratio respective to liver (TBR). The Shrout-Fleiss intra-class correlation coefficient was used to assess reliability between readers. A linear mixed effects model, accounting for within-patient correlations, was used to compare TBR values of primary renal lesions with and without distant metastasis. The time interval between imaging and surgery for all tumors had a median of 77 (Mean: 139; Range: 1-512) days. Intra-class reliability of mean TBR resulted in a mean κ score of 0.93, indicating strong agreement between the readers. The mixed model showed a significant difference in mean TBR among the subtypes (p < 0.0001). Pairwise comparison showed significant differences between pRCC type II and ccRCC (p < 0.0001), pRCC type II and pRCC type I (p = 0.0001), and pRCC type II and oncocytoma (p = 0.0016). Furthermore, a significant difference in FDG uptake was present between primary pRCC type II renal lesions with and without distant metastasis (p = 0.023). pRCC type II lesions demonstrated significantly higher FDG activity than ccRCC, pRCC type I, or oncocytoma. These findings indicate that FDG may prove useful in studying the metabolic activity of renal neoplasms, identifying lesions of highest clinical concern, and ultimately optimizing active surveillance, and personalizing management plans.

Precision Surgery and Kidney Cancer: Knowledge of Genetic Alterations Influences Surgical Management.

Renal cell carcinoma is a term that represents multiple different disease processes, each driven by different genetic alterations, with distinct histology, and biological potential which necessitates divergent management strategies. This review discusses the genetic alterations seen in several forms of hereditary kidney cancer and how that knowledge can dictate when and how to intervene with a focus on the surgical management of these tumors.

An unusual outcome of papillary renal cell carcinoma with lung metastases: a case report and review of literature

BackgroundRenal cell carcinoma (RCC) is a heterogeneous group of malignant epithelial tumors of the kidney. It accounts for more than 90% of all kidney cancers. However, papillary RCC is the second most common histologic subtype representing 10–15% of all RCCs. The mean age of presentation for papillary RCC ranges between 59 and 63 years but more importantly when RCC is diagnosed at a younger age, the possibility of an underlying hereditary kidney cancer syndrome should be considered. RCC potentially metastasizes to many different organs with lung being the commonest site accounting for 45.2%. The treatment for metastatic RCC is mostly multimodal for most patients. However, patients with untreated pulmonary metastases have been observed to have very poor prognosis with a 5-year overall survival rate of only 5% or even less and thus the need to report on the unusual outcome of our patient who had a metastatic disease.Case presentationThe present study reports a papillary renal cell carcinoma with multiple lung metastases in a 31-year-old woman who presented with progressive right flank mass and pain with no chest symptoms. She underwent cytoreductive radical nephrectomy via a right subcostal incision. Patient, however, did not undergo metastasectomy nor palliative systemic therapy and was seen 5 years post-nephrectomy.ConclusionOur patient with metastatic RCC, without undergoing metastasectomy nor palliative systemic therapy, remained stable with 5-year progression-free survival post-cytoreductive nephrectomy.

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate.

Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.

The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population.

PurposeVon Hippel-Lindau (VHL) disease is a hereditary kidney cancer syndrome, with which patients are more likely to get affected by renal cell carcinoma (RCC), pancreatic cyst or tumor (PCT), central nervous system hemangioblastoma (CHB), retinal angiomas (RA), and pheochromocytoma (PHEO). Mutations of VHL gene located in 3p25 may impair the function of the VHL protein and lead to the disease. It’s unclear why obvious phenotype varieties exist among VHL patients. Here we aimed to ascertain whether the mutation types and locations affect the phenotype.MethodsWe enrolled 577 Chinese VHL patients from 211 families and divided them into three groups and six subgroups according to their mutation types and locations. Cox survival analysis and Kaplan-Meier analysis were used to compare intergroup age-related tumor risks.ResultsPatients with nonsense or frameshift mutations that were located before residues 117 of VHL protein (NoF1 subgroup) hold lower age-related risks of VHL associated tumors (HR = 0.638, 95%CI 0.461–0.883, p = 0.007), CHB (HR = 0.596, 95%CI 0.409–0.868, p = 0.007) or PCT (HR = 0.595, 95%CI 0.368–0.961, p = 0.034) than patients whose mutations were located after residues 117 (NoF2 subgroup). Patients in NoF1 subgroup still had lower age-related risks of CHB (HR = 0.652, 95%CI 0.476–0.893, p = 0.008) and PCT (HR = 0.605, 95%CI 0.398–0.918, p = 0.018) compared with those in combined NoF2 subgroup and other truncating mutation patients. NoF1 subgroup correspondingly had a longer estimated median lifespan (64 vs. 55 year, p = 0.037) than NoF2 subgroup. Among patients with missense mutations of VHL, only a small minority (23 of 286 missense mutations carriers) carried mutations involving neither HIF-α binding region nor elongin C binding region, who were grouped in MO subgroup. MO subgroup seemed to have a higher age-related risk of PHEO. In the whole cohort (n = 577), PHEO was an independent protective factor for CHB (p = 0.001) and survival (p = 0.005). RA and CHB failed to predict the age-related risk of each other.ConclusionThe mutation types and locations of VHL gene are associated with phenotypes. Genetic counselors could predict phenotypes more accurately based on more detailed genotype-phenotype correlations. Further genotype-phenotype studies should focus on the prediction of tumor recurrence, progression, and metastasis. The deep molecular mechanism of genotype-phenotype correlation is worth further exploring.

PD45-05 CANCER PREDISPOSING GENES GERMLINE ALTERATIONS IN PATIENTS WITH SPORADIC KIDNEY CANCER

INTRODUCTION AND OBJECTIVE:Hereditary kidney cancer cases represents less than 5% of all renal cell carcinoma (RCC) cases. Germline testing is recommended in patient with early onset (age ≤46 y) an...

Genetic risk assessment for hereditary RCC: Report from the consensus panel meeting.

615 Background: While many genes are now known to be associated with hereditary kidney cancer syndromes, there is a paucity of guidelines or uniform consensus on genetic testing for these patients. An expert panel was organized to assess who, what, when and how patients should be evaluated and what testing should be initiated. Methods: A national, multidisciplinary, panel of experts in urology, medical oncology, clinical geneticists, genetic counselors and patient advocates with background and knowledge in hereditary syndromic kidney cancer convened in person in September 2019. A renal cell carcinoma (RCC) genetic risk assessment questionnaire consisting of 52 questions was compiled prior to the meeting using modified Delphi methodology. The questions were then discussed and reviewed with uniform consensus defined as a minimum of 85% agreement in accordance with the National Comprehensive Cancer Network criteria. Results: The panel consisted of twenty-six attendees represented by urologists (43%), medical oncologist (23%), genetic counselors (13%), clinical geneticists (7%), and patient advocates (3%). The questionnaire consisted of fifty-five statements focusing on who, what, when and how genetic testing should be performed in a patient suspected of hereditary RCC syndrome. A &gt;85% agreement was reached on 30/52 statements with 18/25 (72%) achieving consensus addressing “who”, 2/6 (33%) achieving consensus in “what’ category, 2/7 (29%) in ‘when’ and 4/6 (67%) on how. The questions with least consensus were found in the “what/when?” category with only 4/13 questions with minimum 85% agreement. Specific areas of debate included an age cutoff for prompting a genetic risk assessment as well as need for familial testing in patients with variants of unknown significance. Conclusions: Despite experience of the panel in management of hereditary RCC, the consensus was reached only on 66% of genetic testing. While many issues will need to be discussed further, those statements with consensus may be used to guide physicians and patients on who, what, when and how genetic RCC risk assessment should be performed.

Selecting the surgical approach in complex reoperative partial nephrectomies: Does robotics have a role?

658 Background: Minimally invasive surgery (MIS) has shown equal oncologic efficacy as the open approach for treating small renal masses but results in improved perioperative parameters. Surgical principles also dictate that the open technique should be considered when facing difficult surgeries though this is experience and not evidenced based. The goal of our study is to explore differences in outcomes amongst open or robotic approaches in complex reoperative partial nephrectomies. Methods: 194 patients who had prior renal surgery from 2008 to 2019 were identified, the majority of which presented with multiple tumors due to known or suspected hereditary kidney cancer syndrome. Patients were stratified into the following cohorts based on surgical history: open after open surgery, open after MIS, robotic after open surgery, and robotic after MIS. Perioperative outcomes were compared amongst cohorts. Results: Significant differences were noted in estimated blood loss (EBL), number of tumors resected, and postoperative complications as assessed by Clavien score. Univariate regression analysis of EBL showed that the number of tumors resected (p &lt;.0001, coefficient: 111 ml), number of prior renal procedures (p=.012, coefficient: 419 ml), hilar clamping (p = .015, coefficient: 840 ml), and intended surgical approach (p = .001; coefficient: 905 ml) were significant. On multivariate analysis, number of tumors resected (p&lt;.0001, coefficient: 97 ml) was the only significant factor. Univariate analysis on post-operative complications showed that number of prior surgeries (p = 0.03, OR: 1.5) and final intended approach (p &lt; .0001, OR: 4.6) were significant. On multivariate analysis, the final intended surgical approach (p = .001, OR: 4.3) was shown to be significant. Conclusions: These data show that the surgical approach of prior procedures is not a significant factor that affects perioperative outcomes, but the use of robotic surgery was associated with decreased post-operative complications in reoperative renal surgery . While open surgery will likely continue to be the standard of care for complex reoperative procedures, these data suggest that robotic surgery is safe and well tolerated in select cases.

Clinical predictors of a positive test result in patients undergoing genetic evaluation for a hereditary kidney cancer syndrome.

Guidelines are available to assist providers in identifying patients with renal cell carcinoma (RCC) that may benefit from genetic counselling, however, the evidence for these recommendations lacks support from the literature and controversy remains as to who should be referred. We aimed to delineate risk factors associated with a positive genetic test in a real-life cohort of patients with RCC referred to a regional medical genetics unit for evaluation of a hereditary kidney cancer syndrome. Patients with a diagnosis of RCC referred to Maritime Medical Genetics Service (Nova Scotia, Canada) from 2006-2017 were reviewed using retrospective data. The primary outcome was identification of clinical features that were associated with a positive test result. Logistic regression models were used for analysis. A total of 135 patients were referred to medical genetics for evaluation; 102 patients were evaluated, 75 underwent testing, and 74 were included in the final analysis. Five patients tested positive: three Birt-Hogg-Dubé, one Cowden syndrome, and one Von Hippel-Lindau. Presence of dermatological lesions (specifically fibrofolliculomas) and more than two high-risk features were the only predictors of a positive test result. The presence of dermatological lesions and more than two high-risk features are the only predictors of a positive test result in patients with a suspected hereditary kidney cancer syndrome. These findings are not reflected in current guidelines, and the clinical implementation of our results may improve the identification of high-risk patients for genetic counselling.

Abstract 3688: iPSC-derived cancer organoids recapitulate genomic and phenotypic alterations of c-Met-mutated hereditary kidney cancer

Abstract Patient-specific, tumor-derived organoids represent a powerful novel technology to model cancer, but the requirement of collection of fresh tumor cells and low efficiency of organoid generation represents significant bottlenecks. The induced pluripotent stem cell (iPSC) technology offers the possibility to generate an unlimited and reproducible source of cancer organoids from patient-derived iPSC bearing an oncogenic mutation. We report here for the first time, the generation of patient-specific iPSC-derived kidney organoids in type 1 papillary renal cell carcinoma (PRCC) with hereditary c-met-mutation. To this end we first reprogrammed hematopoietic cells of a patient with type 1 PRCC using Oct4, Sox2, Klf4 and c-Myc. The iPSC cell line generated teratoma in NSG mice and expressed pluripotency markers Tra-1-60 and SSEA-4. As compared control iPSC lines, the c-Met mutated iPSC expressed high levels of phosphorylated c-Met protein. To determine the feasibility of generation of kidney organoids from the iPS cells we have used 3D culture in low attachment cultures giving rise to organoids expressing markers of kidney progenitors (PODXL, LTL) with presence of tight junctions and brush borders in tubular structures at transmission electron microscopy. Importantly, the c-met-mutated kidney organoids expressed PRCC markers in vitro with presence of cells expressing cytokeratin 7 and TFE3. When injected under the kidney capsule of NSG mice, c-met-mutated kidney organoids generated teratomas in which we have found structures with glomerular or tubular origin of such structures with the expression of Nephrin and Cytokeratin 7. Gene expression profiling of c-met-mutated iPSC-derived organoid structures showed striking molecular similarities with signatures found in a large cohort of PRCC patient samples and identified the expression of 11 common genes shared with c-Met-mutated iPSC-derive organoids and primary cancers. Among these, BHLHE40 and KDM4C, well-known factors involved in PRCC pathogenesis, were also expressed in tumors obtained in vivo after transplantation of c-met-mutated kidney organoids in immunodeficient mice. To determine the expression of these two markers discovered by the iPSC-derived organoid technology, we have analyzed tumor biopsies from 5 primary PRCC wit and without c-MET mutation. This analysis showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated organoid transcriptome. These data represent therefore the first proof of concept of the generation of “renal carcinoma in a dish” model using c-met-mutated iPSC-derived organoids, opening new perspectives for discovery of novel disease markers and novel drugs for future precision medicine strategies. Note: This abstract was not presented at the meeting. Citation Format: Jin Wook Hwang, Christophe Desterke, Olivier Feraud, Stephane Richard, Sophie Ferlicot, Virginie Verkarre, Jean Jacques Patard, Julien Loisel-Duwattez, Adlen Foudi, Frank Griscelli, Annelise Bennaceur Griscelli, Ali G. Turhan. iPSC-derived cancer organoids recapitulate genomic and phenotypic alterations of c-Met-mutated hereditary kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3688.

Inherited kidney cancer syndromes

To describe current paradigms for genetic testing, screening, and treatment of patients with inherited kidney cancer syndromes. We describe various new aspects of hereditary kidney cancer. Recent data now support that hereditary kidney cancer may account for 5-8% of kidney cancers diagnosed. Methods of testing have evolved including the introduction of multigene next-generation sequencing panels. We continue to learn more about the natural history and management of classic hereditary cancer syndromes. New emerging conditions with lower kidney cancer penetrance have been recognized adding the growing list of syndromes associated with kidney cancer development. The surgical management strategies of enucleation remain however systemic therapy options are being explored both for localized and advanced settings. Genetic predisposition to kidney cancer is likely more common than once thought. Knowledge of clinical manifestation and genetic testing strategies are needed to properly identify and treat patient and their families.

Long-term response of metastatic hereditary leiomyomatosis and renal cell carcinoma syndrome associated renal cell carcinoma to bevacizumab plus erlotinib after temsirolimus and axitinib treatment failures

BackgroundHereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare hereditary kidney cancer syndrome in which affected individuals are at risk of skin and uterine leiomyomatosis and kidney cancer. HLRCC-associated kidney cancer is a lethal disease with a highly aggressive behavior, and there is no standard treatment option for metastatic disease.Case presentationHere, we report a 29-year-old patient with a locally advanced HLRCC-assiciated RCC. He was administrated temsirolimus initially, then underwent surgical removal of kidney, retroperitoneal lymph nodes, inferior vena cava and tumor thrombi. Unfortunately, multiple liver metastases were confirmed 1 month after surgery, so axitinib was given but failed immediately. We tried bevacizumab plus erlotinib, which achieved long-term good response lasting more than 18 months. He is alive with disease and maintains bevacizumab plus erlotinib treatment.ConclusionThe promising results obtained in this patient suggest that combined bevacizumab plus erlotinib may offer a valid treatment option for advanced HLRCC-associated kidney cancer, even after failures of mTOR inhibitor and/or VEGFR TKI based therapies.

MP42-15 TIMING, INCIDENCE AND MANAGEMENT OF DELAYED BLEEDING AFTER PARTIAL NEPHRECTOMY IN PATIENTS AT RISK FOR RECURRENT, BILATERAL, MULTIFOCAL RENAL TUMORS

INTRODUCTION AND OBJECTIVES:Delayed bleeding is an infrequent complication after partial nephrectomy, with reported rates of 2-3%. Patients with hereditary kidney cancer are often managed with rese...