Hereditary Renal Cell Carcinoma Syndrome Research Articles

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.

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]

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]

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.

PD33-09 MULTI-INSTITUTIONAL REPORT OF PATIENT CHARACTERISTICS AND ONCOLOGIC OUTCOMES FOLLOWING MICROWAVE ABLATION OF BIOPSY-PROVEN RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 May 2022PD33-09 MULTI-INSTITUTIONAL REPORT OF PATIENT CHARACTERISTICS AND ONCOLOGIC OUTCOMES FOLLOWING MICROWAVE ABLATION OF BIOPSY-PROVEN RENAL CELL CARCINOMA Leo Dreyfuss, Arighno Das, Kimberly Maciolek, Rand Wilcox Vanden Berg, Glenn Allen, Jonathan Fainberg, Tudor Borza, Shane Wells, Stephen Culp, E. Jason Abel, and Timothy McClure Leo DreyfussLeo Dreyfuss More articles by this author , Arighno DasArighno Das More articles by this author , Kimberly MaciolekKimberly Maciolek More articles by this author , Rand Wilcox Vanden BergRand Wilcox Vanden Berg More articles by this author , Glenn AllenGlenn Allen More articles by this author , Jonathan FainbergJonathan Fainberg More articles by this author , Tudor BorzaTudor Borza More articles by this author , Shane WellsShane Wells More articles by this author , Stephen CulpStephen Culp More articles by this author , E. Jason AbelE. Jason Abel More articles by this author , and Timothy McClureTimothy McClure More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002584.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: CT-guided thermal ablation is an option for the treatment of small renal masses. Patients with comorbidities may not tolerate extirpative surgery for localized renal cell carcinoma (RCC) and microwave ablation (MWA) may be considered. We report patient characteristics and outcomes following MWA of biopsy-proven RCC at three high-volume centers. METHODS: Consecutive patients with localized, non-metastatic, pathologically confirmed RCC treated with MWA at three centers were included. Images were reviewed by abdominal radiologists experienced with ablation. Contrast-enhanced CT was performed immediately following ablation to confirm technical success. Surveillance included abdominal cross-sectional imaging at 3-6 month intervals for 2 years and yearly thereafter. Local recurrence was defined radiographically as enhancing tumor within the ablation site following complete ablation. RESULTS: 541 ablations were performed in 492 patients. Patients with hereditary RCC syndromes (n=15), prior RCC (n=107), multifocal/bilateral tumors (n= 82), and benign/negative biopsy (n=27) were excluded. Final analysis included 370 patients (median age 68; 139 female) with sporadic, biopsy-proven RCC. 307 patients had cT1a tumors and 63 patients had cT1b or greater tumors. Compared with T1a tumors, patients with T1b tumors had higher body mass index, Charlson Comorbidity index, and ECOG performance status (p<0.05) but did not differ in gender or age. T1b tumors were more likely to be clear cell RCC (p=0.010) and high grade (0.028). 32 patients developed recurrences at a median time of 12 (IQR 6-26) months. Local recurrence free survival in the entire cohort was 88.7% at 36 months, 92.1% (95% CI 86.6-95.5) for T1a and 88.1% (95% CI 69.8-95.7) for T1b. Local recurrence free survival improved to 97.3% (95% CI 93.6-98.9) when repeat ablations were included in the analysis. Metastatic free survival was 98.2% at 36 months for all patients, 98.8% (95% CI 96.4-99.6) for T1a and 94.8% (95% CI 80.2-98.7) for T1b. RCC subtype and tumor grade were not associated with local recurrence in patients with T1a tumors. For T1b patients, high tumor grade was predictive of local recurrence (p=0.037). CONCLUSIONS: In this multi-institutional series of biopsy-proven RCC, metastatic spread was rare following MWA. Local control can be achieved for cT1a and cT1b tumors, though multiple ablation sessions may be necessary. Microwave ablation for cT1b masses may be a viable option for patients with medical comorbidities precluding surgical management. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e556 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Leo Dreyfuss More articles by this author Arighno Das More articles by this author Kimberly Maciolek More articles by this author Rand Wilcox Vanden Berg More articles by this author Glenn Allen More articles by this author Jonathan Fainberg More articles by this author Tudor Borza More articles by this author Shane Wells More articles by this author Stephen Culp More articles by this author E. Jason Abel More articles by this author Timothy McClure More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP24-05 OUTCOMES OF PARTIAL NEPHRECTOMY FOR NON-METASTATIC cT2 RENAL TUMORS: RESULTS FROM A CANADIAN MULTI-INSTITUTIONAL COLLABORATIVE

You have accessJournal of UrologyCME1 May 2022MP24-05 OUTCOMES OF PARTIAL NEPHRECTOMY FOR NON-METASTATIC cT2 RENAL TUMORS: RESULTS FROM A CANADIAN MULTI-INSTITUTIONAL COLLABORATIVE Rahul Bansal, Ryan Sun, Frederic Pouliot, Ranjeeta Mallick, Simon Tanguay, Darrel Drachenberg, Richard Rendon, Alan So, Luke Lavallee, Antonio Finelli, Lucas Dean, Anil Kapoor, Bimal Bhindi, Lori Wood, Naveen Basappa, and Rodney Breau Rahul BansalRahul Bansal More articles by this author , Ryan SunRyan Sun More articles by this author , Frederic PouliotFrederic Pouliot More articles by this author , Ranjeeta MallickRanjeeta Mallick More articles by this author , Simon TanguaySimon Tanguay More articles by this author , Darrel DrachenbergDarrel Drachenberg More articles by this author , Richard RendonRichard Rendon More articles by this author , Alan SoAlan So More articles by this author , Luke LavalleeLuke Lavallee More articles by this author , Antonio FinelliAntonio Finelli More articles by this author , Lucas DeanLucas Dean More articles by this author , Anil KapoorAnil Kapoor More articles by this author , Bimal BhindiBimal Bhindi More articles by this author , Lori WoodLori Wood More articles by this author , Naveen BasappaNaveen Basappa More articles by this author , and Rodney BreauRodney Breau More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002563.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The role of 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 2021. 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 (±1 cm), histology, grade (clear cell and papillary), and necrosis (clear cell). Matched patients were analyzed as clusters. RESULTS: A total of 1347 patients were identified, and 42 PN patients met study criteria who were then matched to 145 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 7.2, 9.2] vs. (8.5 cm [IQR 7.6, 10.3], p=0.048), had higher likelihood of undergoing open surgery (75% vs. 30% p <0.0001), less likely received adrenalectomy (0 vs. 21%, p=0.0001) and had higher likelihood of positive surgical margin (PSM) (10% vs. 1%, p=0.025). Median follow up was not significantly different in either group (3.7yrs [IQR 1.1, 5.4] in PN vs. 2.8yrs [IQR 1.2, 5.6] in RN, p=0.79). During the follow up period, PN patients had higher risk of local recurrence (HR 4.38 95% CI 1.51-12.71) and lower risk of metastasis (HR 0.39; 95% CI 0.16-0.95), improved cancer specific survival (HR 0.65; 95% CI 0.22-1.87) and overall survival (HR 0.47; 0.17-1.27) as compared to RN (Fig. 1). CONCLUSIONS: In this multi-institutional Canadian cohort of patients with non-metastatic cT2 RCC undergoing surgery, PN was associated with higher likelihood of PSM and local recurrence as compared to RN and lower risk of distant metastasis, cancer related death or death from any cause. Despite individual patient matching, there is likely unadjusted selection bias resulting in superior cancer survival associated with PN. Source of Funding: N/A © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e394 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rahul Bansal More articles by this author Ryan Sun More articles by this author Frederic Pouliot More articles by this author Ranjeeta Mallick More articles by this author Simon Tanguay More articles by this author Darrel Drachenberg More articles by this author Richard Rendon More articles by this author Alan So More articles by this author Luke Lavallee More articles by this author Antonio Finelli More articles by this author Lucas Dean More articles by this author Anil Kapoor More articles by this author Bimal Bhindi More articles by this author Lori Wood More articles by this author Naveen Basappa More articles by this author Rodney Breau More articles by this author Expand All Advertisement PDF DownloadLoading ...

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 ...

A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression

Aims. Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare aggressive renal malignancy associated with hereditary leiomyomatosis and RCC syndrome (HLRCC). Tumors exhibiting heterogeneous (ie, patchy) FH loss by immunohistochemistry have rarely been described, may be diagnostically challenging, and have never been the focus of a study. We aimed to investigate the FH mutational status of FH-deficient RCC with heterogeneous versus complete FH loss, to characterize additional genetic drivers, and to evaluate 2SC immunohistochemistry in this setting. Methods and Results. We studied FH-deficient RCC with heterogeneous (n = 3) and complete (n = 4) FH loss. Targeted next-generation sequencing (NGS) was performed on all tumors. No patients had a known history of HLRCC. All tumors had histological features within the morphologic spectrum described for FH-deficient RCC. All 7 tumors were immunoreactive for 2SC. Molecularly, all 7 tumors revealed multiple hits involving the FH locus resulting in complete loss of wild-type alleles. All tumors with heterogeneous FH loss harbored FH missense variants within domain 2 of the protein, and each had concomitant copy neutral loss of heterozygosity (CN-LOH). In complete FH loss tumors, FH alterations included splice variants with concomitant loss of heterozygosity (n = 2) and homozygous gene deletions (n = 2). Other non-recurrent alterations included biallelic alterations of TP53, NF2, SMAD4 and activation of PIK3CA. Conclusions. Our series highlights how heterogeneous FH loss (patchy positive staining) is an important staining pattern to recognize since it is compatible with a diagnosis of FH-deficient RCC and should prompt additional ancillary studies (confirmatory 2SC immunohistochemistry and/or molecular testing) and genetic evaluation.

Hereditary renal cell tumors: Clinicopathologic importance

Hereditary renal cancer syndromes represent approximately 5% of renal malignancies and have distinctive clinical, histopathologic, and genetic features. Next-generation sequencing and other molecular testing methods have uncovered several hereditary renal cancer syndromes. Several autosomal dominant hereditary renal cell carcinoma (RCC) syndromes, including those related to germline pathogenic variants in VHL, BAP1, MITF, MET, FH, TSC1/TSC2, FLCN, SDH, and CDC73 have been confirmed. FH- and BAP1-related RCCs are associated with more aggressive disease. Identifying the clinical and pathological features in these hereditary RCC syndromes is important as, relative to familial cohorts, these patients require early screening and intervention and regular surveillance to improve their clinical prognosis and long-term outcomes. More importantly, identification of these syndromes plays a vital role in personalized management and systemic treatment selection in this modern era of precision medicine. Ongoing studies have demonstrated that treatment based on genetic pathway targeting is a promising approach for hereditary renal cancer management. This review describes updates in the diagnostic criteria for and management of familial kidney cancer syndromes.

Response to systemic therapy in fumarate hydratase–deficient renal cell carcinoma

PurposeFumarate hydratase–deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population. MethodsWe performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan–Meier method. ResultsTwenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received “other antiangiogenics” (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for “other antiangiogenics,” and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0–95.0). ConclusionsWe report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.

PTEN Hamartoma Tumor Syndrome: A Case of Renal Cell Carcinoma in a Young Female

PTEN Hamartoma-Tumor-Syndrome (PHTS) describes a series of conditions characterized by germline-mutation of the PTEN tumor-suppressor gene. PHTS patients have an increased lifetime risk of multiple malignancies, including thyroid, breast, and endometrial cancers. PHTS patients also have 20-30 fold increased risk of renal cell carcinoma (RCC) compared to age-matched controls. As with many hereditary RCC syndromes, tumors present early and multifocally. We present a case of one of the youngest patients diagnosed with RCC in PHTS and review the urologic implications of this syndrome.

NCCN Guidelines Insights: Kidney Cancer, Version 1.2021.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Fumarate Hydratase–Deficient Renal Cell Carcinoma: A Review

Abstract Fumarate hydratase (FH)–deficient renal cell carcinoma (RCC) has emerged in recent years as a subtype of renal tumors that show diverse morphologic patterns with predominance of papillary architecture. Most of these tumors show high-grade cytologic features and at least focally prominent eosinophilic macronucleoli with perinuclear halos. Infrequently, these tumors show low-grade oncocytic cytologic features. Fumarate hydratase–deficient RCCs are characterized by inactivating FH gene mutations resulting in FH loss and 2-succinocysteine [2SC] accumulation, demonstrable by immunohistochemistry. A vast majority of these tumors occur in the setting of hereditary leiomyomatosis and RCC syndrome. Fumarate hydratase–deficient RCCs show slight male preponderance and present at relatively younger age. These tumors are often locally advanced at the time of presentation. Prospective recognition of these tumors upon histologic examination is of paramount importance not only for the appropriate management of the patient but also for a potential to detect undiagnosed hereditary leiomyomatosis and RCC syndrome in at-risk family members.

MP08-07 GENOMIC PROFILING OF CT1A CLEAR CELL RENAL CELL CARCINOMA FOR PREDICTING AGGRESSIVE PATHOLOGY

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP08)1 Apr 2020MP08-07 GENOMIC PROFILING OF CT1A CLEAR CELL RENAL CELL CARCINOMA FOR PREDICTING AGGRESSIVE PATHOLOGY Zeyad Schwen*, Hiten Patel, Michael Biles, Joseph Cheaib, Ridwan Alam, Michael Gorin, Michael Johnson, Mohamad Allaf, Alexander Baras, and Phillip Pierorazio Zeyad Schwen*Zeyad Schwen* More articles by this author , Hiten PatelHiten Patel More articles by this author , Michael BilesMichael Biles More articles by this author , Joseph CheaibJoseph Cheaib More articles by this author , Ridwan AlamRidwan Alam More articles by this author , Michael GorinMichael Gorin More articles by this author , Michael JohnsonMichael Johnson More articles by this author , Mohamad AllafMohamad Allaf More articles by this author , Alexander BarasAlexander Baras More articles by this author , and Phillip PierorazioPhillip Pierorazio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000828.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A greater emphasis has been placed on illuminating the mutational landscape of renal cell carcinoma (RCC) to better understanding the underlying tumor biology to predict tumor aggressiveness. While much of the focus has been on advanced and metastatic RCC, we aimed at identifying whether somatic mutations are also prognostic for aggressive pathology in the small renal mass for better patient selection for active surveillance or surgical treatment. METHODS: From an IRB-approved institutional tissue biorepository, surgically removed cT1a (<4cm) clear cell RCC (ccRCC) specimens were selected. Those with any nodal or metastatic disease as well as hereditary or genetic RCC syndromes were excluded. DNA was isolated from formalin-fixed paraffin-embedded tissue and sent for targeted sequencing using an 8-gene panel including VHL, SETD2, PBRM1, KDM5c, BAP1, PTEN, and TP53. Mutational type and frequencies were recorded for each specimen and were evaluated for associations with high tumor grade (ISUP 3, 4) and upstaging to pT3a. RESULTS: 70 consecutive tissue samples from cT1a renal masses were isolated for analysis. Patients were mostly male (61.3%) and more frequently underwent a partial nephrectomy (82.3%). Median tumor size was 2.5cm (IQR 1.9-3.3cm). 88.6% (62/70) of tumors had at least one mutation with VHL (39/70, 55.7%) and SETD2 (55/70, 78.6%) as the most frequent mutations (Table 1). Notably, we found BAP1 mutations to be significant associated with high grade (ISUP 3 or 4) or upstaging to pT3a (p < 0.036) and PBRM1 was significantly associated with upstaging (p < 0.047) (Figure 1). Also, BAP1 and KDM5c had a high PPV for high grade or upstaging (71% and 75%, respectively). The number of mutations and type of mutation were not found to be associated with upstaging or high grade pathology. CONCLUSIONS: Somatic mutations are common in cT1a ccRCC tumors and BAP1 and PBRM1 mutations were found to be associated with higher tumor grade and upstaging to pT3a which may be useful for better selecting patients for active surveillance. Larger, prospective studies are required. Source of Funding: National Kidney Foundation of Maryland © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e107-e108 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zeyad Schwen* More articles by this author Hiten Patel More articles by this author Michael Biles More articles by this author Joseph Cheaib More articles by this author Ridwan Alam More articles by this author Michael Gorin More articles by this author Michael Johnson More articles by this author Mohamad Allaf More articles by this author Alexander Baras More articles by this author Phillip Pierorazio More articles by this author Expand All Advertisement PDF downloadLoading ...

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.

Clinical and morphologic review of 60 hereditary renal tumors from 30 hereditary renal cell carcinoma syndrome patients: lessons from a contemporary single institution series.

Hereditary renal cell carcinoma syndromes (HRCCS) are characterized by the presence of pathogenic germline variants that predispose patients to renal cell carcinomas as well as additional extra-renal manifestations. The importance of identifying HRCCS patients cannot be overemphasized, as patients and their families can begin surveillance for syndrome-associated manifestations once identified. The present study is a retrospective clinical and morphologic review of 60 hereditary renal tumors from 30 HRCCS patients treated at our institution with either Von Hippel-Lindau disease (VHL), Birt-Hogg-Dubé syndrome (BHD), tuberous sclerosis complex (TSC), hereditary leiomyomatosis and renal cell cancer syndrome, or succinate dehydrogenase (SDH) deficiency syndrome. Hereditary renal cell carcinoma syndromes kidney tumors often demonstrate specific morphologic features, characteristic background changes in renal parenchyma, and extra-renal manifestations, which, when recognized by the pathologist, can trigger genetic testing referral for specific familial cancer syndromes. Our study demonstrates the majority of tumors were consistent with the anticipated clinicopathologic profile of renal tumors found within HRCCS patients, although we found some unique characteristics within this cohort including a case of clear cell papillary renal cell carcinoma within a VHL patient, and a unique renal tumor with tubulopapillary features present in a patient with a germline SDHD mutation. Additionally, although the literature reports the presence of epithelioid angiomyolipoma (AML) as a common occurrence in TSC patients, our cohort of 3 patients with AMLs demonstrated only classic features. The findings we describe facilitate pathologist-based recognition of HRCCS and can prompt genetic evaluation for relevant patients.

Real-world outcomes of genetic testing in a GU genetics clinic and evaluation of current guidelines.

668 Background: Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)-related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU cancers, but there are limited data on the performance of these guidelines in clinical practice, and the association between testing outcome and clinical and familial features that may delineate a heritable syndrome. The purpose of this study is to determine the most common indications for ordering genetic testing in a GU Genetics Clinic and evaluate the relationship between the indication for germline testing and outcome. Methods: An IRB-approved retrospective chart review was performed for 350 patients seen in a GU Genetics Clinic at a single comprehensive cancer center from 2014-2018. Subgroups of patients were formed based on their indication for genetic testing. Exact binomial tests were used to compare the proportion of patients with a positive (pathogenic or likely pathogenic) germline variant for those with vs. without each indication. Results: All patients had a genetic evaluation due to a personal or family history of GU cancer. The majority (324 of 350, 92.5%) were evaluated for either renal cell carcinoma (RCC) or prostate cancer (PrCa). Among patients seen for RCC-related evaluation (n = 159), 23 patients (14.5%) tested positive. Meeting published clinical criteria for a hereditary RCC syndrome significantly predicted positive testing ( P&lt; 0.001). No other indication for testing, including RCC diagnosis ≤ 46 years, predicted for positive germline genetic test results. No positive patients were identified by age of RCC onset alone. Among patients seen for PrCa-related evaluation (n = 173), 13 (7.5%) individuals tested positive; all positive variants were in ATM or BRCA2. A single patient (1/13) was identified by metastatic PrCa status alone. Conclusions: Our data suggest current algorithms lack specificity for selecting individuals with RCC or PrCa at risk for germline mutations, and need to be revised. Evaluation of pedigrees and identifying presence of syndromic features are essential and increase the probability of identifying individuals at risk for harboring a germline mutation.

Management of renal cell carcinoma in young patients and patients with hereditary syndromes.

Individuals that present with renal cell carcinoma at an early age deserve special attention because they are more likely to harbor an inherited predisposition and may require unique treatment strategies. In recent years, there has been a significant increase in the number of characterized hereditary syndromes, many of which may predispose to kidney cancer. Although hereditary kidney cancer accounts for only 5-8% of kidney cancers, it should be considered in anyone with an early age of onset. These uncommon presentations should prompt consideration for genetic evaluation for germline alterations or somatic alterations associated with translocations. Treatment of kidney cancer in young individuals must also consider the late risks of nephron loss, the uncertainty with long-term follow-up after ablation, and the need for years of surveillance not only for the treated tumor but for de novo lesions in a patient with a greater risk of multifocality. Early age of onset should raise concern for a hereditary renal cell carcinoma syndrome and should prompt consideration for genetic counseling to review personal and family history and determine if testing is indicated. Despite advancements in this field, significant work remains to fully delineate the management strategies for young individuals with and without hereditary cancer syndromes.

Structured assessment and followup for patients with hereditary kidney tumour syndromes.

Optimal clinical assessment and subsequent followup of patients with or suspected of having a hereditary renal cell carcinoma syndrome (hRCC) is not standardized and practice varies widely. We propose protocols to optimize these processes in patients with hRCC to encourage a more uniform approach to management that can then be evaluated. A review of the literature, including existing guidelines, was carried out for the years 1985-2015. Expert consensus was used to define recommendations for initial assessment and followup. Recommendations for newly diagnosed patients' assessment and optimal ages to initiate followup protocols for von Hippel Lindau disease (VHL), hereditary papillary renal cancer (HPRC), hereditary leiomyomatosis with renal cell carcinoma (HLRCC), Birt-Hogg-Dubé syndrome (BHD), familial paraganglioma-pheochromocytoma syndromes (PGL-PCC), and tuberous sclerosis (TSC) are proposed. Our proposed consensus for structured assessment and followup is intended as a roadmap for the care of patients with hRCC to guide healthcare providers. Although the list of syndromes included is not exhaustive, the document serves as a starting point for future updates.