Hereditary Renal Cell Carcinoma Research Articles

The Prevalence and Radiologic Features of Renal Cancers Associated with FLCN, BAP1, SDH, and MET Germline Mutations.

Purpose To investigate the prevalence of FLCN, BAP1, SDH, and MET mutations in an oncologic cohort and determine the prevalence, clinical features, and imaging features of renal cell carcinoma (RCC) associated with these mutations. Secondarily, to determine the prevalence of encountered benign renal lesions. Materials and Methods From 25 220 patients with cancer who prospectively underwent germline analysis with a panel of more than 70 cancer-predisposing genes from 2015 to 2021, patients with FLCN, BAP1, SDH, or MET mutations were retrospectively identified. Clinical records were reviewed for patient age, sex, race/ethnicity, and renal cancer diagnosis. If RCC was present, baseline CT and MRI examinations were independently assessed by two radiologists. Summary statistics were used to summarize continuous and categorical variables by mutation. Results A total of 79 of 25 220 (0.31%) patients had a germline mutation: FLCN, 17 of 25 220 (0.07%); BAP1, 22 of 25 220 (0.09%); SDH, 39 of 25 220 (0.15%); and MET, one of 25 220 (0.004%). Of these 79 patients, 18 (23%) were diagnosed with RCC (FLCN, four of 17 [24%]; BAP1, four of 22 [18%]; SDH, nine of 39 [23%]; MET, one of one [100%]). Most hereditary RCCs demonstrated ill-defined margins, central nonenhancing area (cystic or necrotic), heterogeneous enhancement, and various other CT and MR radiologic features, overlapping with the radiologic appearance of nonhereditary RCCs. The prevalence of other benign solid renal lesions (other than complex cysts) in patients was up to 11%. Conclusion FLCN, BAP1, SDH, and MET mutations were present in less than 1% of this oncologic cohort. Within the study sample size limits, imaging findings for hereditary RCC overlapped with those of nonhereditary RCC, and the prevalence of other associated benign solid renal lesions (other than complex cysts) was up to 11%. Keywords: Familial Renal Cell Carcinoma, Birt-Hogg-Dubé Syndrome, Carcinoma, Renal Cell, Paragangliomas, Urinary, Kidney © RSNA, 2024.

Percutaneous microwave ablation on management of hereditary renal cell carcinoma in Von Hippel–Lindau disease

Background The effect of microwave ablation (MWA) for the renal cell carcinoma (RCC) in Von Hippel-Lindau (VHL) disease is unclear. Objective To assess the safety, Technique efficacy, renal function and oncological outcome of MWA for RCC in VHL patients. Methods Consecutive patients with RCCs in VHL disease treated by MWA were retrospectively collected from November 2009 to October 2020. The technical efficacy rate and complications were assessed. The outcomes of pre- and post-ablative eGFR were compared. The local recurrent-free survival (LRFS), renal-cancer-free survival (RCFS), cancer-specific survival (CSS), overall survival (OS) and complications were presented. Results A total of 10 patients (mean age, 39.0 years ± 10.7 [SD]; 3 women) with 28 RCCs (mean tumor size, 3.0 cm ± 0.34; mean tumor volume, 20.7 mL ± 43.3) treated with MWA were included. Th median follow-up time was 52 months(IQR:27-80). The overall technical efficacy rate was 100% with no major complications occurred. No significant statistical difference between pre-ablative and postablative creatinine level (102.0 µmol/L ± 30.4 vs 112.3 µmol/L ± 38.7, p = 0.06), but the pre-ablative eGFR level was significantly higher than the post-ablative eGFR (78.0 mL/(min*1.73m2) ± 28.6 vs 72 mL/(min*1.73m2) ± 31.4, p = 0.04), with the mean decrease of 5.86 ml/(min*1.73m2). The local recurrent-free survival(LRFS) and renal-cancer-free survival (RCFS) were 100% and 60%, respectively. The cancer specifical survival (CSS) and overall survival (OS) were 95.5% and 100%, respectively. Conclusion Microwave ablation is a safe and feasible method for the treatment of RCC in VHL disease, preserving renal function and yielding satisfactory oncological outcomes.

Hereditary Renal Cell Carcinoma: Is Age an Independent Criterion for Genetic Testing? A Large Cohort from a Latin America Referral Center.

Although age younger than 46 years has been an independent criterion for genetic testing in hereditary renal cell carcinoma (hRCC), there is a lack of evidence in the literature. This study aims to analyze whether a 46-year-old cut-off should be considered an independent genetic testing criterion and to elucidate risk factors predicting a positive genetic test. Observational study from January 2010 to December 2021. All patients under 46 years with a non-metastatic kidney mass and surgical indication were included. We assume patients who relapse in the first 5 years of follow-up could have a positive genetic test. As risk factors for relapse, ergo positive genetic test, we consider those patients who presented multifocal, bilateral, or previous renal tumor. Of 2,232 nephrectomies for kidney cancer, 301 patients met the inclusion criteria. The median follow-up was 60 months (IQR 29-101). The estimated five-year RFS was 94.4% (95% CI 91.3-97.5). Tumor size, previous renal tumor, multifocality, bilaterality, and pT3 or pT4 stage were independent recurrence risk factors. Genetic testing was performed on 24 patients. 10 patients had pathogenic variants in the test, 8 of which recurred during their life. 46-year-old cut-off has shown low performance in genetic testing. Therefore, we recommend that it be considered only if other hRCC risk criteria exist. Multifocality, bilaterality, and previous renal tumor could predict a positive genetic test.

Genomic profiles of renal cell carcinoma in a small Chinese cohort.

Our aim was to describe the molecular characteristics of Renal Cell Carcinoma (RCC) and develop a small panel of RCC-associated genes from a large panel of cancer-related genes. Clinical data of 55 patients with RCC diagnosed in four hospitals from September 2021 to August 2022 were collected. Among the 55 patients, 38 were diagnosed with clear cell RCC (ccRCC), and the other 17 were diagnosed with non-clear cell RCC (nccRCC), including 10 cases of papillary renal cell carcinoma, 2 cases of hereditary leiomyomatosis and RCC syndrome (HLRCC), 1 eosinophilic papillary RCC, 1 tubular cystic carcinoma, 1 TFE3 gene fusion RCC, and 2 RCC with sarcomatoid differentiation. For each patient, 1123 cancer-related genes and 79 RCC-associated genes were analyzed. The most frequent mutations in a large panel of 1123 cancer-related genes in the overall population of RCC patients were VHL (51%), PBRM1 (35%), BAP1 (16%), KMT2D (15%), PTPRD (15%), and SETD2 (15%). For ccRCC patients, mutations in VHL, PBRM1, BAP1, and SERD2 can reach 74%, 50%, 24%, and 18%, respectively, while for nccRCC patients, the most frequent mutation was FH (29%), MLH3 (24%), ARID1A (18%), KMT2D (18%), and CREBBP (18%). The germline mutation rate in all 55 patients reached 12.7% (five with FH, one with ATM, and one with RAD50). The small panel containing only 79 RCC-associated genes demonstrated that mutations of VHL, PBRM1, BAP1, and SETD2 in ccRCC patients were 74%, 50%, 24%, and 18% respectively, while for the nccRCC cohort, the most frequent mutations were FH (29%), ARID1A (18%), ATM (12%), MSH6 (12%), BRAF (12%), and KRAS (12%). For ccRCC patients, the spectrum of mutations by large and small panels was almost the same, while for nccRCC patients, the mutation spectrum showed some differences. Even though the most frequent mutations (FH and ARID1A) in nccRCC were both demonstrated by large panels and small panels, other less frequent mutations such as MLH3, KMT2D, and CREBBP were not shown by the small panel. Our study revealed that nccRCC is more heterogeneous than ccRCC. For nccRCC patients, the small panel shows a more clear profile of genetic characteristics by replacing MLH3, KMT2D, and CREBBP with ATM, MSH6, BRAF, and KRAS, which may help predict prognosis and make clinical decisions.

#3697 FAMILIAL PAPILLARY RENAL CELL CARCINOMA: A CASE REPORT

Abstract Background and Aims The incidence of Renal Cell Carcinoma (RCC) is the 9th commonest cancer worldwide. It originates from the renal tubular epithelium and to date has been subclassified into five different categories. Of which, papillary carcinoma is one subclassification and it includes two variants: sporadic and hereditary. This case report aims to outline a rare case of hereditary papillary RCC and the implications for the family involved. Method We performed a retrospective assessment of clinical and radiological characteristics of the index patient and affected relatives. Genetic diagnosis and management have been summarised. Results A 62-year-old male (II.1) was diagnosed with RCC after presenting with right-sided flank pain and multiple complex cystic lesions within both kidneys. A kidney biopsy revealed a papillary structure with foamy histocytes and clear cell-type epithelium clusters. Immunostaining of tumour cells demonstrated CK7 and P504S positivity consistent with RCC. Subsequently, he underwent bilateral nephrectomies and being rendered anephric, was commenced on haemodialysis. He underwent deceased donor renal transplantation four years later at the age of 66 (HLA 1:2:1, CMV -/-, cRF 35%) and remains dialysis independent six years on. After the diagnosis of the index patient, his son (III.1) was found to have multifocal papillary RCC, having also presented with flank pain, but this time in his 30s (Fig. 1). Patient III.1 underwent genetic testing which revealed a missense variant in the MET gene (NM_000245.4 c.3308G>A; p.Gly1103Glu). The variant affects a highly conserved residue in the Tyrosine Kinase domain of the MET protein. Pathogenic activating variants are associated with RCC. Identification of the same variant in the affected father with bilateral disease allowed classification of the variant as likely pathogenic according to the ACMG criteria [1]. The father has seven children, all of whom have now been tested. 5/7 of them have been found to carry the likely pathogenic MET missense variant. Of the 4 asymptomatic carriers, all are under surveillance by regular renal imaging and (one has had radiofrequency ablation). Conclusion The case outlines a rare form of hereditary RCC and the implications that detection of the genetic variant has meant in terms of early diagnosis of disease. Incidence of RCC is increasing worldwide. Hereditary papillary RCC is rare, it is typically inherited in an autosomal dominant pattern. Germline mutations in the MET proto-oncogene are located at 7q31, which encodes for the tyrosine kinase signaling pathway. Variants lead to uncontrolled activation of MET protein and aberrant cell growth [2]. Discussion Hereditary papillary RCC has an estimated incidence of < 1:1500000, its rarity highlighted by the fact that only ∼35 families have been reported worldwide in literature. In these cases it exhibits 100% penetrance, with patients developing renal cell carcinoma typically between their fifth and sixth decade [3]. We would like to acknowledge the family involved in this case report. As with many cancers, early diagnosis is helped by detection of a genetic variant, leading to improved long-term disease-free survival. In the case of metastatic papillary RCC 2-year survival is still estimated at 18% (3).

Frequency of pathogenic germline variants in cancer susceptibility genes in 841 renal cell carcinoma cases.

e16551 Background: Hereditary Renal cell carcinoma (RCC) syndrome accounts for approximately 5-10% of all kidney cancers. However, the genetic architecture of susceptibility to RCC is not well defined. In this study, we investigated the prevalence and spectrum of pathogenic/likely pathogenic germline variants of cancer susceptibility genes in unselected RCC patients in the real-world Chinese population. Methods: We retrospectively profiled the germline mutations of 841 unselected RCC patients using a next-generation sequencing panel consisting of 808 cancer-related genes. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Genomic alterations include single nucleotide variations (SNV), short insertions/deletions (INDEL) and copy number variations (CNV). Results: Within 841 unselected RCC patients included in this study, 132 germline pathogenic/likely pathogenic (P/LP) variants were identified in 125 patients (14.9%), of which 114 (13.6%) were mutations of SNV/INDEL and 11 (1.3%) were CNV. Overall, 46 patients (5.5%) carried mutations of hereditary RCC syndrome-associated genes such as VHL (13, 1.5%), FH (13, 1.5%) and FLCN (8, 1.0%). Interestingly, variants in other cancer-predisposition genes not traditionally associated with RCC occurred in 9.4% of the unselected series, including 55 (6.5%) patients carried mutations in DNA damage (DDR)-related genes (e.g., MUTYH, CHEK2 and BRCA1/2) and the other 24 (2.9%) had germline mutations of non-DDR-related genes (e.g., SPINK1 and APC). The median age of patients with mutations of RCC syndrome-associated genes was 38 (range 19-77), while the median age of patients with mutations of other cancer-predisposition genes was 52(range 22-82). Furthermore, in patients older than 46 years, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes were 1.9% and 6.7%, respectively. Notably, among 125 patients with identified germline mutations, nearly half (56, 44.8%) did not meet the recommended criteria for genetic testing. Conclusions: Our findings confirm a high prevalence of pathogenic germline variants in genes associated with both hereditary RCC and other cancer predispositions in the unselected Chinese RCC population. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing and expand the range of genes in RCC population with advanced age.

Germline mutations in hereditary renal cell carcinoma (RCC) genes among 32,240 patients with all cancer types.

4559 Background: Germline pathogenic variants (PVs) in VHL, FH, BAP1 and others cause hereditary syndromes with increased risk of renal cell carcinoma (RCC). Defining the clinical spectrum of these syndromes has been limited by ascertainment bias and their relative rarity. Using a large population of cancer patients who underwent germline and somatic tumor testing, we analyzed the landscape of germline PVs in RCC genes in individuals with all cancer types. Methods: We identified patients with germline PVs in RCC genes ( VHL, FH, SDHB, MET, FLCN, BAP1) in the MSK-IMPACT cohort, an institutional protocol of patients who had somatic and germline sequencing. The MITF E318K variant was analyzed separately given its uncertain role in RCC risk. Objectives were to determine whether patients met clinical criteria for their respective hereditary syndromes, analyze biallelic inactivation in all tumor types, and explore underrecognized cancer associations. Fisher test was used to compare frequency of variants to population. Results: Of 32,240 patients who consented to germline results, 55% were female; most common cancer types were breast (n=3600), pancreas (n=3554), prostate (n=3427), with 1166 (3.6%) with RCC. 110 (0.34%) had a germline variant in a RCC syndrome gene ( BAP1=26, SDHB=24, FH=24, FLCN=19, VHL=16, MET=1). Of 110 germline positive, 56% met clinical criteria for their hereditary syndrome, and 40% had RCC. For VHL, FH, SDHB and MET, a high proportion of patients met criteria for their hereditary syndromes, but this was much less for FLCN (Birt-Hogg-Dubé) and BAP1. Biallelic inactivation in the tumor, supporting causality, was very high except in FLCN. Possible novel cancer associations were liver cancer in BAP1 (n=5;19%) and colon cancer in FLCN (n=4;17%). Additionally, 114 patients had the MITF E318K variant; which was not enriched in RCC cases (only 1 RCC) compared to other cancers or population control (odds ratio 0.45; p-value = 0.16, 95% confidence interval: 0.1 -1.2). Conclusions: Germline analysis in a large pan-cancer cohort identifies a high prevalence of patients with hereditary RCC syndromes, variability in clinical phenotype and suggestion of novel cancer associations. The low number of MITF E318K variant carriers in RCC cases calls into question its role in RCC risk and warrants further study. [Table: see text]

Blood-based molecular profiling of Chinese patients with advanced renal cell carcinoma.

e16550 Background: The therapeutic landscape of renal cell carcinoma (RCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy in real time. Next-generation sequencing (NGS)-based profiling of circulating tumor DNA (ctDNA) shows promise for noninvasive detection. To evaluate the clinical utility of ctDNA analysis in RCC, we aimed to analyze the molecular characteristics of RCC using ctDNA by NGS. Methods: A total of 189 plasma samples and 26 matched tumor tissues from Chinese patients with advanced renal cell carcinoma (n = 189) were analyzed by Acornmed panel with 808 cancer-related genes, and matched white blood cell as germline comparators. Results: Overall, 29 germline mutations were detected in 14.3% (27/189) patients, such as TSC2 (5/189, 2.65%), FH (3/189, 1.6%) and VHL (2/189, 1.1%), of which 10 germline aberrations in DNA damage repair (DDR) genes were detected in 5.3% patients (10/18). In addition, a total of 1590 somatic variations were identified in 96.8% (183/189) ctDNA, including 1278 nonsynonymous single nucleotide variants, 126 small insertions or deletions, 75 copy number variations. And the median blood tumor mutation burden (bTMB) was 4.36 mut/Mb. Mutations in VHL (36/189, 19.4%) were the most prominent variation, followed by those in TP53 (19/189, 10.0%), BAP1 (12/189, 6.3%), PBRM1 (10/189, 5.3%) and SETD2 (7/189, 3.7%). Moreover, totals of 154 clinically actionable mutations from 92 patients (48.7%) were identified. In 26 patients with both tumor tissues and plasma samples, sequencing detected alterations in 100% (26/26) tumor tissue DNA (tDNA) and 96.2% (25/26) ctDNA, respectively. Furthermore, 29.6% of mutations of tissues were founded in ctDNA, and 21.6% of mutations of ctDNA were detected in tissues. Among them, 73.1% (19/26) patients had at least one overlapping variant called by tDNA and ctDNA. The most common shared mutation was VHL (5/26, 19.2%). Meanwhile, four shared copy number variants were detected in two patients (15.4%). Conclusions: Our study contributes to understand the molecular characteristics of RCC using ctDNA, which is a viable option for tissue when tissue is difficult to obtain. Furthermore, ctDNA testing by NGS is helpful for drug selection and provides more effective treatment options for RCC, particularly for hereditary RCC.

MP47-18 OUTCOMES OF PERCUTANEOUS RENAL CRYOABLATION IN A LARGE COHORT OVER 15 YEARS

You have accessJournal of UrologyCME1 Apr 2023MP47-18 OUTCOMES OF PERCUTANEOUS RENAL CRYOABLATION IN A LARGE COHORT OVER 15 YEARS Zachary A. Valley, Evan Allarie, Steven Lu, Richard Cormack, Michael Welsh, Bryan J. Donnelly, and Kamaljot S. Kaler Zachary A. ValleyZachary A. Valley More articles by this author , Evan AllarieEvan Allarie More articles by this author , Steven LuSteven Lu More articles by this author , Richard CormackRichard Cormack More articles by this author , Michael WelshMichael Welsh More articles by this author , Bryan J. DonnellyBryan J. Donnelly More articles by this author , and Kamaljot S. KalerKamaljot S. Kaler More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003293.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Historically, the standard of care for renal cell carcinoma (RCC) has been partial nephrectomy (PN) or radical nephrectomy (RN). Image-guided percutaneous cryoablation (PCA) of renal masses has emerged as a nephron-sparing, minimally invasive alternative. In this study, we aim to assess outcomes of percutaneous renal cryoablation at a single centre over 15 years. METHODS: Patients who underwent PCA of renal masses from 2006 to 2022 were included with no exclusions. All patients had cross-sectional imaging prior to the procedure and most underwent biopsy at the time of procedure. Cryoprobe placement and ice-ball formation was monitored via computed tomography (CT) imaging during the procedure. Data were collected via electronic medical record review, as well as pre-, intra-, and post-procedure imaging review. Data included demographics, tumor characteristics, pathology, local recurrence and metastatic disease rates, complications, pre- and post-procedure renal function and blood counts, co-morbidities, and mortality rate of patients in follow-up. RESULTS: This study included 598 patients in the analysis with a median age of 65.1 years and median follow-up of 39 months (Table 1). The average size of tumor was 2.7 cm. Overall local recurrence rate was 4.8% including surgically resected and hereditary RCC. Average nephrometry score was 6.1. Median time to local recurrence was 2.0 years. Five percent of patients made up 52% of the recurrences. Overall survival rate was 82.3% at time of analysis. Cancer-specific survival overall was 97.3%. Average length of time to discharge was 28.2 hours. The Clavien-Dindo 3+ complication rate was 2.3%. Overall metastatic rate was 1.8% and 0.7% in patients with no recurrence. CONCLUSIONS: PCA outcomes in this large cohort with no exclusions and long-term follow-up revealed an overall low recurrence rate, low complication rate, and an acceptable metastatic rate. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e651 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zachary A. Valley More articles by this author Evan Allarie More articles by this author Steven Lu More articles by this author Richard Cormack More articles by this author Michael Welsh More articles by this author Bryan J. Donnelly More articles by this author Kamaljot S. Kaler More articles by this author Expand All Advertisement PDF downloadLoading ...

PD07-10 OUTCOMES OF PARTIAL NEPHRECTOMY FOR NON-METASTATIC cT2 RENAL TUMORS: RESULTS FROM A CANADIAN MULTI-INSTITUTIONAL COLLABORATIVE

You have accessJournal of UrologyCME1 Apr 2023PD07-10 OUTCOMES OF PARTIAL NEPHRECTOMY FOR NON-METASTATIC cT2 RENAL TUMORS: RESULTS FROM A CANADIAN MULTI-INSTITUTIONAL COLLABORATIVE Rahul Bansal, Raees Cassim, Ryan Sun, Ranjeeta Mallick, Antonio Finelli, Simon Tanguay, Darrel Drachenberg, Frederic Pouliot, Luke Lavallee, Alan So, Ricardo Rendon, Lori Wood, Anil Kapoor, Aly-Khan Lalani, Naveen Basappa, Lucas Dean, Bimal Bhindi, Georg Bjarnason, and Rodney Breau Rahul BansalRahul Bansal More articles by this author , Raees CassimRaees Cassim More articles by this author , Ryan SunRyan Sun More articles by this author , Ranjeeta MallickRanjeeta Mallick More articles by this author , Antonio FinelliAntonio Finelli More articles by this author , Simon TanguaySimon Tanguay More articles by this author , Darrel DrachenbergDarrel Drachenberg More articles by this author , Frederic PouliotFrederic Pouliot More articles by this author , Luke LavalleeLuke Lavallee More articles by this author , Alan SoAlan So More articles by this author , Ricardo RendonRicardo Rendon More articles by this author , Lori WoodLori Wood More articles by this author , Anil KapoorAnil Kapoor More articles by this author , Aly-Khan LalaniAly-Khan Lalani More articles by this author , Naveen BasappaNaveen Basappa More articles by this author , Lucas DeanLucas Dean More articles by this author , Bimal BhindiBimal Bhindi More articles by this author , Georg BjarnasonGeorg Bjarnason More articles by this author , and Rodney BreauRodney Breau More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003231.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The role of partial nephrectomy (PN) is not well defined for cT2 renal cell carcinoma (RCC) as compared to radical nephrectomy (RN). The aim of this study was to examine oncological outcomes of PN as compared to RN for non-metastatic cT2 RCC. METHODS: The Canadian Kidney Cancer information system was used to define patients who underwent surgery for non-metastatic cT2 RCC from January 2011 to October 2022. Patients with clear-cell, papillary, and chromophobe RCC were included. Other histology, multiple tumours, and hereditary RCC syndrome patients were excluded. Each PN patient was individually matched to RN up to 1:4 depending on availability of patients based on tumor size (+/-1cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. RESULTS: A total of 1523 patients were identified, and 50 PN patients met study criteria who were then matched to 185 RN patients. Both groups had similar age, gender, smoking status, BMI, Charlson comorbidity index score, symptoms at presentation, baseline eGFR, hemoglobin and pathological characteristics. PN patients had smaller tumors (7.6 cm [IQR 23] vs 8.4 [IQR 2.4], p=0.0479), had higher likelihood of undergoing open surgery (72.9% vs 31.8%, p<0.0001) and less likely received adrenalectomy (2% vs 24.3%, p=0.0004). Positive surgical margin rates were similar in both groups (8.2% in PN vs 3.4% in RN, p=0.2296). Median follow up was not significantly different in either group (3.6 yrs [IQR 4.7] in PN vs 3.3 [4.7] yrs in RN, p=0.975). During the follow up period, PN patients had higher risk of local recurrence (HR 3.0, 95%CI 1.08-8.37) and lower risk of metastasis (HR 0.36, 95%CI 0.15-0.88), overall survival (HR 0.36, 95%CI 0.18-1.78) as compared to RN. Cancer specific recurrence was similar between both groups (HR 0.56 ,95%CI 0.18,1.78). PN patients preserved more GFR than RN patients (-14.4 [SD 17.9] vs -23.7[SD 15], p=0.0006). Complications rates were similar between PN and RN (18% vs 8.65%, p=0.0571). CONCLUSIONS: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN compared to RN was associated with higher local recurrence, lower risk of distant metastasis, and death from any cause with similar complications and better preservation of renal function. Despite individual patient matching, there is likely unadjusted selection bias resulting in superior cancer survival associated with PN. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e166 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rahul Bansal More articles by this author Raees Cassim More articles by this author Ryan Sun More articles by this author Ranjeeta Mallick More articles by this author Antonio Finelli More articles by this author Simon Tanguay More articles by this author Darrel Drachenberg More articles by this author Frederic Pouliot More articles by this author Luke Lavallee More articles by this author Alan So More articles by this author Ricardo Rendon More articles by this author Lori Wood More articles by this author Anil Kapoor More articles by this author Aly-Khan Lalani More articles by this author Naveen Basappa More articles by this author Lucas Dean More articles by this author Bimal Bhindi More articles by this author Georg Bjarnason More articles by this author Rodney Breau More articles by this author Expand All Advertisement PDF downloadLoading ...

Outcomes of partial nephrectomy for non-metastatic cT2 renal tumors: Results from a Canadian multi-institutional collaborative.

690 Background: The role of partial nephrectomy (PN) is not well defined for cT2 renal cell carcinoma (RCC) as compared to radical nephrectomy (RN). The aim of this study was to examine oncological outcomes of PN as compared to RN for non-metastatic cT2 RCC. Methods: The Canadian Kidney Cancer information system was used to define patients who underwent surgery for non-metastatic cT2 RCC from January 2011 to October 2022. Patients with clear-cell, papillary, and chromophobe RCC were included. Other histology, multiple tumours, and hereditary RCC syndrome patients were excluded. Each PN patient was individually matched to RN up to 1:4 depending on availability of patients based on tumor size (+/- 1cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. Results: A total of 1523 patients were identified, and 50 PN patients met study criteria who were then matched to 185 RN patients. Both groups had similar age, gender, smoking status, BMI, Charlson comorbidity index score, symptoms at presentation, baseline eGFR, hemoglobin and pathological characteristics. PN patients had smaller tumors (7.6 cm [IQR 2] vs 8.4 [IQR 2.4], p=0.05), had higher likelihood of undergoing open surgery (72.9% vs 31.8%, p&lt;0.0001) and less likely received adrenalectomy (2% vs 24.3%, p=0.0004). Positive surgical margin rates were similar in both groups (8.2% in PN vs 3.4% in RN, p=0.2). Median follow up was not significantly different in either group (3.6 yrs [IQR 4.7] in PN vs 3.3 [4.7] yrs in RN, p=0.9). During the follow up period, PN patients had higher risk of local recurrence (HR 3.0, 95%CI 1.08-8.37), lower risk of distant metastasis (HR 0.36, 95%CI 0.15-0.88), better cancer specific survival (HR 0.56, 95%CI 0.18-1.78) and overall survival (HR 0.36, 95%CI 0.11-1.19) and as compared to RN. At 6 months and beyond after surgery, PN patients had less decline in eGFR than RN patients (-16.6 [SD 21.1] vs -24.4[SD 16.2], p=0.0002). Complications rates between PN and RN were (18% vs 9%, p=0.057). Conclusions: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN compared to RN was associated with slightly higher risk of peri-operative complications, better preservation of renal function, and higher risk of local recurrence. The lower risk of distant metastasis and death was likely from residual confounding unaccounted for in the individual patient match. [Table: see text]

Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma.

Germline pathogenic variants are estimated to affect 3-5% of patients with renal cell carcinoma (RCC). The identification of patients with hereditary RCC is important for cancer screening and treatment guidance. Whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was used to analyze germline mutations in 123 patients with RCC admitted to Department of Urology, The Third Medical Center of Chinese PLA General Hospital. Chi-square test (χ2) was used to analyze relationship between clinicopathologic parameters and germline mutations. A total of 13 (10.57%) patients carried pathogenic or likely pathogenic germline mutations in 10 cancer predisposition genes, including VHL, FH, FLCN, SDHB, MUTYH, RAD51C, NBN, RAD50, FANCI, and FANCM. A total of 6 of these 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair. Patients harboring pathogenic germline mutations tended to have an earlier RCC onset. The prevalence of deleterious mutations was higher in patients with bilateral or multifocal RCC compared to patients without bilateral or multifocal RCC. Patients with non-clear cell RCC (nccRCC) were significantly more likely to have RCC-associated gene mutations. To our knowledge, this is the first report of pathogenic germline mutations in the FANCI and FANCM genes and heterozygous germline missense mutation in exon 5 of the FH gene c.563A>T:p.N188I in RCC. Young RCC patients, patients with bilateral or multifocal RCC, or patients with nccRCC are more likely to have pathogenic/potentially pathogenic germline mutations.

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.

Imaging Features of Renal Masses to Select Optimal Candidates for Tumor Enucleation Partial Nephrectomy.

The goal of this paper was to critically evaluate preoperative findings that optimally select candidates for renal tumor enucleation partial nephrectomy. Tumor enucleation has been widely accepted as a management option for patients with chronic kidney disease, hereditary renal cell carcinoma, or multifocal disease. Recent evidence suggests safety and efficacy in the management of routine small renal masses. With recent advances in imaging, the literature for ruling out aggressive renal cell carcinoma and selection for tumor enucleation is robust. As the incidence of renal cell carcinoma rises, partial nephrectomy continues to be the mainstay of treatment for localized renal cell carcinoma. Tumor enucleation maximizes preservation of renal parenchyma without hindering oncologic outcomes. It is important to recognize key tumor radiologic findings which urologists may use to optimize patient selection for tumor enucleation.

P114 - Hereditary renal cell carcinoma surveillance protocols - a review and new surveillance protocol proposal

P114 - Hereditary renal cell carcinoma surveillance protocols - a review and new surveillance protocol proposal

Hereditary Renal Cell Carcinoma

BACKGROUND: Hereditary renal cell carcinoma (RCC) is a complex and rapidly evolving topic as there is a growing body of literature regarding inherited syndromes and mutations associated with an increased risk of RCC. OBJECTIVES: We sought to systematically review 13 hereditary syndromes associated with RCC; von Hippel-Lindau Disease associated RCC (VHLRCC), BAP-1 associated clear cell RCC (BAPccRCC), Familial non-von Hippel Lindau clear cell RCC (FccRCC), Tuberous Sclerosis Complex associated RCC (TSCRCC), Birt-Hogg-Dub e ´ Syndrome associated RCC (BHDRCC), PTEN Hamartoma Tumor Syndrome associated RCC (PHTSRCC), Microphthalmia-associated Transcription Family translocation RCC (MiTFtRCC), RCC with Chromosome 6p Amplification (TFEBRCC), Autosomal Dominant Polycystic Kidney Disease associated RCC (ADPKDRCC), Hereditary Leiomyomatosis associated RCC (HLRCC), Succinate Dehydrogenase RCC (SDHRCC), Hereditary Papillary RCC (HPRCC), and ALK-Rearrangement RCC (ALKRCC). RESULTS: Hereditary RCC is generally associated with an early age of onset, multifocal and/or bilateral lesions, and aggressive disease course. VHLRCC, BAPccRCC, FccRCC, and certain mutations resulting in SDHRCC are associated with clear cell RCC (ccRCC). HPRCC is associated with Type 1 papillary RCC. HLRCC is associated with type 2 papillary RCC. BHDRCC is associated with Chromophobe RCC. TSCRCC, PHTSRCC, MiTFtRCC, TFEBRCC, ADPKDRCC, certain SDHRCC and ALKRCC have variable histology. CONCLUSIONS: There has been tremendous advancement in our understanding of the pathophysiology of hereditary RCC. Ongoing research will refine our understanding of hereditary RCC and its therapeutic targets.

Abstract 2970: Oncometabolites confer vulnerabilities in NAD biosynthesis via NAPRT gene silencing

Abstract Cancer associated mutations in citric acid cycle enzymes cause overproduction of 2-hydroxyglutarate (2HG), fumarate, or succinate, commonly referred to as oncometabolites. These oncometabolite producing mutations are prevalent in 70% of gliomas, &amp;gt;76% of hereditary leiomyomatosis and renal cell carcinoma, and &amp;gt;25% of paraganglioma and pheochromocytomas, respectively. These oncometabolite producing cancers harbor vulnerabilities in multiple cellular pathways because oncometabolites competitively inhibit alpha ketoglutarate dependent dioxygenases. This group of enzymes includes the ten eleven translocation (TET) family of enzymes, which catalyze locus specific DNA demethylation. Thus, oncometabolite producing cancers have been shown to exhibit global DNA hypermethylation, which drastically alters gene expression in the cell and is thought to occur via TET inhibition. Cells with isocitrate dehydrogenase 1 (IDH1) mutations, which produce 2HG, have loss of expression of a critical NAD biosynthesis enzyme, nicotinate phosphoribosyltransferase (NAPRT). We show that in addition to IDH1 mutant cells, fumarate hydratase (FH)-deficient isogenic cell lines, which overproduce fumarate, show loss of NAPRT expression, which can be targeted by nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. The goal of our work is to determine if this NAPRT silencing is present in many oncometabolite producing cancers, elucidate the mechanism of silencing, and test therapies to target this vulnerability in NAD biosynthesis. FH-deficient cancer cell lines show reduction of NAPRT mRNA levels by qRT-PCR and absence of protein by western blot, suggesting a reduction in NAPRT transcription. In addition, FH-deficient cell lines exhibit synthetic lethality in short term cell viability assays when treated with NAMPT inhibitor, FK866, which inhibits a parallel NAD biosynthesis pathway. Cell viability is not rescued by nicotinic acid supplementation in FH-deficient lines while parental lines are rescuable, validating the loss of functional NAPRT in only FH-deficient lines. Furthermore, patient samples of FH-deficient renal cell carcinomas show higher NAPRT promoter methylation compared to healthy tissue via methylation array. Ongoing studies are investigating the role of TET1/2/3 enzymes in NAPRT promoter methylation. Together, these results suggest that hypermethylation of the NAPRT promoter is associated with silencing of NAPRT expression in FH-deficient cancers, which can be therapeutically targeted through NAMPT inhibition. Citation Format: Katelyn Noronha, Jiayu Liang, Ranjit Bindra. Oncometabolites confer vulnerabilities in NAD biosynthesis via NAPRT gene silencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2970.

Abstract 3112: Metabolic hallmarks of rare renal cell carcinoma patient-derived xenograft models

Abstract Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare but highly aggressive malignancies that are often refractory to the therapies used for the more common RCCs. FH-deficient RCC most often occurs in individuals with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) and is characterized by loss of FH activity, a key metabolic enzyme. Bevacizumab plus erlotinib (B+E) is a preferred first-line therapy for FH-deficient RCC. RMC is characterized by loss of SMARCB1, which is involved in ATP-dependent chromatin remodeling. Platinum-based chemotherapy consisting of either cisplatin or carboplatin plus paclitaxel is the preferred first-line therapy for RMC. We developed patient-derived xenograft (PDX) models of tumors exposed to the commonly used first-line therapies to allow functional characterization of the metabolic hallmarks of treatment-experienced RMC and FH-deficient RCC. Methods: Resected tumor tissue was immediately implanted into NSG male and female mice. After tumor engraftment, animals were euthanized, and the tumor tissue implanted into another set of NSG mice. PDX tissues were confirmed to be genetically identical to the original patient tissue by short tandem repeat analysis. Histology was confirmed to be identical between original patient tumor and PDX by a trained clinical pathologist. Four tumors from each PDX model and four normal human kidney tissue samples were analyzed using reverse phase protein array (RPPA). Expression of proteins shown to be highly expressed by RPPA were further validated by Western blots. Results: We successfully generated one PDX model for RMC and one for FH-deficient RCC, respectively. The RMC model was generated from a 28-year old male with sickle cell trait, who had previously received cisplatin plus paclitaxel followed carboplatin plus paclitaxel. His lesion was characterized as ypT3apN1pMx and histology was consistent with RMC. The FH-deficient RCC model was generated from a 24-year-old female with HLRCC, who had been previously treated with B+E. Her lesion was characterized as pT3apN1pM1 and histology consistent with FH-deficient RCC. Germline testing revealed a R233H pathogenic mutation in the FH gene. RPPA revealed higher expression of hexokinase II (10x HLRCC, 16x RMC), lactate dehydrogenase A (27x HLRCC, 17x RMC), and glutaminase (4x HLRCC) in PDX tissue compared to normal kidney tissue. Western blots confirmed higher expression of glutaminase 1 in both HLRCC and RMC compared to normal kidney. Furthermore, we observed substantially higher hypoxia inducible factor 2α (HIF2α) protein expression in PDX tissue from FH-deficient RCC compared to RMC PDX tumors and normal kidney. Conclusions: Our study revealed distinct metabolic features in PDX models of FH-deficient RCC following treatment with B+E, and of platinum-experienced RMC, these differences may confer targetable vulnerabilities. Citation Format: Manuel Ozambela, Alberto Pieretti, Graciela M. Nogueras Gonzalez, Tapati Maity, Lei Wang, Carolyn De La Cerda, Breanna Alonzo, Luis Segarra, Angelita Alaniz, Priya Rao, Nizar Tannir, Jose A. Karam, Christopher G. Wood, Pavlos Msaouel, Niki M. Zacharias. Metabolic hallmarks of rare renal cell carcinoma patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3112.

Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma

BackgroundFH-deficient renal cell carcinoma (RCC) is a rare and exceptionally aggressive RCC subtype. There is currently limited understanding of the molecular alterations, pathogenesis, survival outcomes, and systemic therapy efficacy for this cancer. ObjectiveTo perform a retrospective multicenter analysis of molecular profiling and clinical outcomes for patients with FH-deficient RCC, with an emphasis on treatment response to first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI/TKI) versus bevacizumab plus erlotinib (Bev/Erlo) combination therapy in patients with advanced disease. Design, setting, and participantsThe study included 77 cases of FH-deficient RCC from 15 centers across China. Outcome measurements and statistical analysisClinical characteristics, molecular correlates, 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed. Results and limitationsA total of 77 patients were identified, including 70 cases with a germline FH alteration (hereditary leiomyomatosis RCC syndrome [HLRCC]-associated RCC) and seven patients with somatic FH loss. Recurrent pathogenic alterations were found in NF2 (six/57, 11%), CDH1 (six/57, 11%), PIK3CA (six/57, 11%), and TP53 (five/57, 8.8%). Sixty-seven patients were evaluable for response to first-line systemic therapy with Bev/Erlo (n = 12), TKI monotherapy (n = 29), or ICI/TKI (n = 26). ICI/TKI combination therapy was associated with more favorable overall survival on systemic treatment (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04–0.90) and progression-free survival on first-line therapy (HR 0.22, 95% CI 0.07–0.71) compared to Bev/Erlo combination therapy. The main limitation is the retrospective study design. ConclusionsWe described the genomic characteristics of FH-deficient RCC in an Asian population and observed a favorable response to ICI/TKI combinational therapy among patients with advanced disease. Patient summaryThis real-world study provides evidence supporting the antitumour activity of combining molecular targeted therapy plus immunotherapy for kidney cancer deficient in fumarate hydratase. Further studies are needed to investigate the efficacy of this combination strategy in this rare cancer.

PD18-10 GERMLINE TESTING IN RENAL CELL CARCINOMA: CAN ENRICHMENT FEATURES HELP PREDICT GERMLINE ALTERATIONS?

You have accessJournal of UrologyCME1 May 2022PD18-10 GERMLINE TESTING IN RENAL CELL CARCINOMA: CAN ENRICHMENT FEATURES HELP PREDICT GERMLINE ALTERATIONS? Alexis Rompre-Brodeur, Nikhil Gopal, Jeunice Owens-Walton, Bradley Webster, Michael Daneshvar, Christopher Ricketts, Cathy Vocke, Laura Schmidt, Beth Ryan, W. Marston Linehan, and Mark W. Ball Alexis Rompre-BrodeurAlexis Rompre-Brodeur More articles by this author , Nikhil GopalNikhil Gopal More articles by this author , Jeunice Owens-WaltonJeunice Owens-Walton More articles by this author , Bradley WebsterBradley Webster More articles by this author , Michael DaneshvarMichael Daneshvar More articles by this author , Christopher RickettsChristopher Ricketts More articles by this author , Cathy VockeCathy Vocke More articles by this author , Laura SchmidtLaura Schmidt More articles by this author , Beth RyanBeth Ryan More articles by this author , W. Marston LinehanW. Marston Linehan More articles by this author , and Mark W. BallMark W. Ball More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002556.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal cell carcinoma (RCC) resulting from a germline alteration accounts for 5-8% of RCC cases. Patients can present enrichment features that may help predict germline alterations, including early onset (EO) defined as age of diagnosis ≤46, bilateral multifocal (BMF), or familial history of renal cancer (FRC). Current recommendations for germline testing suffer from lack of high-quality evidence. We sought to characterize the frequency of germline alterations in these potentially enriched populations. METHODS: Patients treated at our institution from 2016-2021 tested with commercial germline panels for hereditary RCC genes were analyzed. Patients with personal or family history of hereditary RCC syndrome and patients with no history of a solid kidney tumor were excluded. Comparative statistical analysis, multivariate logistic regression and odd ratios (OR) were used to determine which group had the highest frequency of germline alterations. RESULTS: Over the study period, 249 eligible patients underwent RCC germline testing. Of these, 221 had at least one potential enrichment features, including 110 with EO, 145 BMF and 64 FRC. Panel results were positive in 37(14.9%) patients, negative in 171(68.7%), or presented a variant of uncertain significance (VUS) in 41(16.5%). Additional enrichment features increased the proportion of positive results; patients with no features had positive results in 7.1% of cases, 1 feature 11.9%, 2 features 19.7% and 3 features 36.4%. Each additional enrichment feature increased the odds of identifying a germline alteration by OR=2.12 (95%CI:1.28-3.62, p=0.04). In a multivariate logistic regression model, individual enrichment features had the following OR for germline alterations: FRC OR=2.92 (95%CI:1.35-6.31) p=0.006; BMF OR=1.68 p=0.199; EO OR=1.82 p=0.118. Simultaneous occurrence of EO+FRC was associated with an OR=2.89 (95%CI:1.03-7.65) p=0.036. CONCLUSIONS: Patients with early onset, bilateral multifocal or familial history of renal cancer are enriched populations with more frequent germline alterations than patients without one of these features. The odds of a germline alteration doubles with each additional enrichment feature. These findings support germline panel testing in these enriched populations. Source of Funding: Intramural Research Program, NCI, NIH © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e347 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexis Rompre-Brodeur More articles by this author Nikhil Gopal More articles by this author Jeunice Owens-Walton More articles by this author Bradley Webster More articles by this author Michael Daneshvar More articles by this author Christopher Ricketts More articles by this author Cathy Vocke More articles by this author Laura Schmidt More articles by this author Beth Ryan More articles by this author W. Marston Linehan More articles by this author Mark W. Ball More articles by this author Expand All Advertisement PDF DownloadLoading ...