Familial 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.

Family History and Risk of Renal Cell Carcinoma: A National Multiregister Case-Control Study.

Our purpose was to investigate the association between family history of renal cell carcinoma (RCC) and RCC risk. RCC cases diagnosed in Sweden between 2005 and 2014 and 10 matched controls were identified using the Renal Cell Cancer Database Sweden, with linkage to the Multigeneration Register and the Swedish Cancer Registry. The association between a family history of RCC and RCC was investigated, overall and by sex and age groups. Among 9416 RCC cases, 294 (3.1%) had 1 or more parent or sibling (first-degree relative [FDR]) with RCC. Median age at diagnosis for cases with an affected FDR was 65 years (IQR 59-71) and 68 years (IQR 60-75) for all cases. The proportion of women was significantly higher among familial RCC compared to sporadic RCC (44.6% vs 38.5%, P = .035). RCC was twice as likely with 1 or more FDR with RCC (OR 1.9; CI 1.65-2.16). Stratified analysis showed an OR of 2.4 for women (CI 1.93-2.92) and 1.6 for men (CI 1.35-1.93). Two or more FDRs was associated with a sixfold increased risk (95% CI 2.37-15.5). Familial RCC was strongly associated with bilateral and multifocal tumors (OR 5.5; CI 2.36-13.0, OR 3.5; CI 1.89-6.49). In this Swedish data set, 3.1% of RCC patients have 1 or more FDR diagnosed with RCC. There was no statistical difference in median age between sporadic RCC and familial RCC. Having 1 or more FDR with RCC approximately doubles the risk of RCC with a higher risk increase for women than for men. People with 2 FDRs with RCC constitute a small high-risk group that may benefit from screening.

MiT/TFE Family Renal Cell Carcinoma.

The microphthalmia-associated transcription factor/transcription factor E (MiT/TFE) family of transcription factors are evolutionarily conserved, basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors, consisting of MITF, TFEB, TFE3, and TFEC. MiT/TFE proteins, with the exception of TFEC, are involved in the development of renal cell carcinoma (RCC). Most of the MiT/TFE transcription factor alterations seen in sporadic RCC cases of MiT family translocation renal cell carcinoma (tRCC) are chimeric proteins generated by chromosomal rearrangements. These chimeric MiT/TFE proteins retain the bHLH-Zip structures and act as oncogenic transcription factors. The germline variant of MITF p.E318K has been reported as a risk factor for RCC. E 318 is present at the SUMOylation consensus site of MITF. The p.E318K variant abrogates SUMOylation on K 316, which results in alteration of MITF transcriptional activity. Only a few cases of MITF p.E318K RCC have been reported, and their clinical features have not yet been fully described. It would be important for clinicians to recognize MITF p.E318K RCC and consider MITF germline testing for undiagnosed familial RCC cases. This review outlines the involvement of the MiT/TFE transcription factors in RCC, both in sporadic and hereditary cases. Further elucidation of the molecular function of the MiT/TFE family is necessary for better diagnosis and treatment of these rare diseases.

Redo Robotic Partial Nephrectomy for Recurrent Renal Tumors: A Multi-Institutional Analysis.

Introduction: As the experience with robot-assisted partial nephrectomy (RAPN) grows, the indications have expanded to incorporate previously operated ipsilateral kidneys with recurrent renal masses. We sought to analyze the outcomes of redo RAPN in patients with a recurrent renal mass. Methods: Using a multi-institutional series, the data of 72 patients who underwent RAPN for a recurrent renal mass between 2010 and 2020 were retrospectively analyzed. Patients with familial renal cell carcinoma and multiple renal tumors were excluded. Major complication was defined by Clavien grade ≥3. The median follow-up was 28.5 months. Baseline demographics, clinical and tumor characteristics, and perioperative and postoperative outcomes are reported. Results: Our cohort consisted of a combination of previous thermal ablation (19.6%), laparoscopic (19.6%), open (26.1%), and robotic (34.8%) partial nephrectomy. The median R.E.N.A.L. score was 8. Twenty percent had hilar tumors and 9.7% had a solitary kidney. RAPN was completed in all cases. Two cases (2.8%) were converted to open surgery. None of the cases were converted to radical nephrectomy intraoperatively. One patient underwent radical nephrectomy postoperatively because of bleeding. Transfusion rate was 5.9% and major complication rate was 8.3%. Median length of stay was 3 days. Estimated glomerular filtration rate preservation was 78.7% at discharge and 90.8% at 1-year follow-up. Positive surgical margin rate was 8.3%. Overall, distant recurrence was seen in 11 patients (15.3%), however, only 1 patient had local progression (1.4%). Conclusion: In experienced hands, RAPN is an effective approach to treat select cases of locally recurrent renal masses with promising perioperative and functional outcomes. Patients should be carefully monitored for distant recurrence.

Robotic partial nephrectomy for management of renal mass in patients with a solitary kidney: can we expand the indication to T2 and T3 disease?

Management of complex renal masses is challenging in a solitary kidney setting. We retrospectively compared oncological and renal functional outcomes between robotic and open partial nephrectomy (PN) in patients with a pT2-pT3 renal mass and a solitary kidney. From a multi-institutional series, we identified 20 robotic partial nephrectomies (RPN) and 15 open partial nephrectomies (OPN) patients confirmed to have a pT2 or pT3 renal cancer. Surgeries were performed between January 2012 and July 2019. Patients with familial renal cell carcinoma, prior ipsilateral PN, or multiple ipsilateral synchronous tumors were excluded from the analysis. Baseline characteristics, perioperative and postoperative outcomes were compared using χ2 test, Fisher's Exact Test, Mann-Whitney U Test, and Student's t-test. Baseline characteristics were comparable. Cold ischemia was utilized more in the open group (92.9% vs. 15.8%, P<0.001). OPN group had a longer ischemia time (48.9 min vs. 27.3 min, P<0.001), a higher major complication rate (38.5% vs. 11.1%, P=0.009), and a higher length of stay was (5 vs. 3.5 days, P=0.023). Positive surgical margin rate was comparable (20% OPN vs. 15% RPN; P=1.000). At a mean follow up of 21 months local recurrence rates (1 OPN vs. 2 RPN, P=1.000) were comparable, chronic kidney disease upstaging rate (46.7% OPN vs. 45.0% RPN, P=0.922) and estimated glomerular filtration rate preservation at one year (75.2%% in OPN vs. 79.1% RPN, P=0.707) were comparable. In select cases and experienced hands, the robotic approach offers a reasonable alternative to open surgery in patients with pT2 and pT3 tumors and a solitary kidney.

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

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

PD64-06 REDO ROBOTIC PARTIAL NEPHRECTOMY FOR RECURRENT RENAL MASSES: A MULTI-INSTITUTIONAL ANALYSIS

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy VI (PD64)1 Sep 2021PD64-06 REDO ROBOTIC PARTIAL NEPHRECTOMY FOR RECURRENT RENAL MASSES: A MULTI-INSTITUTIONAL ANALYSIS Alp T. Beksac, Umberto Carbonara, Mahmoud Abou Zeinab, Sij Hemal, Margaret Meagher, Alessandro Tafuri, Gabriele Tuderti, Alessandro Antonelli, Riccardo Autorino, Giuseppe Simone, Ithaar Derweesh, and Jihad Kaouk Alp T. BeksacAlp T. Beksac More articles by this author , Umberto CarbonaraUmberto Carbonara More articles by this author , Mahmoud Abou ZeinabMahmoud Abou Zeinab More articles by this author , Sij HemalSij Hemal More articles by this author , Margaret MeagherMargaret Meagher More articles by this author , Alessandro TafuriAlessandro Tafuri More articles by this author , Gabriele TudertiGabriele Tuderti More articles by this author , Alessandro AntonelliAlessandro Antonelli More articles by this author , Riccardo AutorinoRiccardo Autorino More articles by this author , Giuseppe SimoneGiuseppe Simone More articles by this author , Ithaar DerweeshIthaar Derweesh More articles by this author , and Jihad KaoukJihad Kaouk More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002108.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: As the experience with robotic partial nephrectomy (RPN) grows, the indications have expanded to incorporate previously operated ipsilateral kidneys with recurrent renal masses. We sought to analyze the outcomes of redo RPN in patients with a recurrent renal mass. METHODS: Using a multi-institutional series, the data of 72 patients who underwent RPN for a recurrent renal mass between 2010 and 2020 was retrospectively analyzed. Patients with familial renal cell carcinoma and multiple renal tumors were excluded. Major complication defined by Clavien grade >2. Median follow up was 28.5 months. Baseline demographics, clinical and tumor characteristics, perioperative and postoperative outcomes are reported. RESULTS: Our cohort consisted of a combination of previous thermal ablation, laparoscopic, open and robotic surgeries. Median RENAL score was 8. In our cohort, 20% had hilar tumors and 9.7% had a solitary kidney. Partial nephrectomy was completed in all cases. Two cases (2.8%) were converted to open surgery. None of the cases were converted to radical nephrectomy intraoperatively. One patient underwent radical nephrectomy postoperatively due to bleeding. Transfusion rate was 5.9% and major complication rate was 8.3%. Median length of stay was 3 days. Acute kidney injury was 35.1% at discharge, however eGFR preservation was 90.8% at one year follow up. Positive surgical margin rate was 9.5%. Recurrence was seen in 14 patients (15.2%), however only one patient had local recurrence (1.4%). CONCLUSIONS: In experienced hands, RPN is an effective approach to treat recurrent renal masses with promising perioperative and functional outcome. Patients should be carefully monitored for distant recurrence. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1145-e1146 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alp T. Beksac More articles by this author Umberto Carbonara More articles by this author Mahmoud Abou Zeinab More articles by this author Sij Hemal More articles by this author Margaret Meagher More articles by this author Alessandro Tafuri More articles by this author Gabriele Tuderti More articles by this author Alessandro Antonelli More articles by this author Riccardo Autorino More articles by this author Giuseppe Simone More articles by this author Ithaar Derweesh More articles by this author Jihad Kaouk More articles by this author Expand All Advertisement Loading ...

PD64-09 COMPARATIVE EVALUATION OF ONCOLOGIC OUTCOMES ACCORDING TO THE ANATOMIC LOCATION OF SURGICAL MARGIN POSITIVITY AFTER PARTIAL NEPHRECTOMY

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy VI (PD64)1 Sep 2021PD64-09 COMPARATIVE EVALUATION OF ONCOLOGIC OUTCOMES ACCORDING TO THE ANATOMIC LOCATION OF SURGICAL MARGIN POSITIVITY AFTER PARTIAL NEPHRECTOMY Alp T. Beksac, Soodong Kim, Umberto Carbonara, Margaret Meagher, Alessandro Tafuri, Mahmoud Abou Zeinab, Louis Lenfant, Alessandro Antonelli, Riccardo Autorino, Ithaar Derweesh, and Jihad Kaouk Alp T. BeksacAlp T. Beksac More articles by this author , Soodong KimSoodong Kim More articles by this author , Umberto CarbonaraUmberto Carbonara More articles by this author , Margaret MeagherMargaret Meagher More articles by this author , Alessandro TafuriAlessandro Tafuri More articles by this author , Mahmoud Abou ZeinabMahmoud Abou Zeinab More articles by this author , Louis LenfantLouis Lenfant More articles by this author , Alessandro AntonelliAlessandro Antonelli More articles by this author , Riccardo AutorinoRiccardo Autorino More articles by this author , Ithaar DerweeshIthaar Derweesh More articles by this author , and Jihad KaoukJihad Kaouk More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002108.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We sought to assess if the anatomical location of positive surgical margins (PSM) can affect the oncological outcomes following partial nephrectomy (PN). METHODS: From a multi-institutional dataset, we performed a retrospective analysis of 115 patients who were found to have PSM following PN. Surgeries were performed between from January 2010 to May 2020. Patients with benign pathology, less than 6 months follow up, baseline metastatic disease, bilateral tumors, familial renal cell carcinoma, and pathological node positive disease were excluded from analysis. Patients with PSM were stratified into two groups according to the anatomical location (parenchymal invasion, sinus fat invasion). Due to uneven sample size a 1:2 matched pair analysis was performed (by cT stage) to limit confounding effect of stage on recurrence. Demographics, clinical and tumor characteristics, and poncological outcomes were compared using Chi-square, Fisher’s exact, Mann-Whitney U, and student’s t tests. Kaplan-Meier analysis performed to analyze recurrence free survival (RFS). RESULTS: Overall 84 patients were included in analysis (56 parenchymal vs. 28 sinus). Median follow-up was 25 months (IQR 11-41). Baseline characteristics were comparable between the two groups. Pathological tumor size was comparable. In the parenchymal group, more patients had multifocal PSM, whereas more patients had pT3a upstaging in the sinus group. Local recurrence rate was higher in the sinus group (17.9% vs. 10.9%, p=0.377), however this association did not reach statistical significance. Distant recurrence rate was comparable as well (5.5% vs. 7.1%, p=0.76). Kaplan-Meier analysis did not show any difference in terms of RFS (p=0.68). CONCLUSIONS: At 25 months follow up, the location of positive surgical margin did not alter distance recurrence rates following PN. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1147-e1148 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alp T. Beksac More articles by this author Soodong Kim More articles by this author Umberto Carbonara More articles by this author Margaret Meagher More articles by this author Alessandro Tafuri More articles by this author Mahmoud Abou Zeinab More articles by this author Louis Lenfant More articles by this author Alessandro Antonelli More articles by this author Riccardo Autorino More articles by this author Ithaar Derweesh More articles by this author Jihad Kaouk More articles by this author Expand All Advertisement Loading ...

Clinical and Molecular Characterization of Microphthalmia-associated Transcription Factor (MITF)-related Renal Cell Carcinoma

To characterize the clinical presentation, genomic alterations, pathologic phenotype and clinical management of microphthalmia-associated transcription factor (MITF) familial renal cell carcinoma (RCC), caused by a member of the TFE3, TFEB, and MITF family of transcription factor genes. The clinical presentation, family history, tumor histopathology, and surgical management were evaluated and reported herein. DNA sequencing was performed on blood DNA, tumor DNA and DNA extracted from adjacent normal kidney tissue. Copy number and gene expression analyses on tumor and normal tissues were performed by Real-Time Polymerase chain reaction. TCGA gene expression data were used for comparative analysis. Protein expression and subcellular localization were evaluated by immunohistochemistry. Germline genomic analysis identified the MITF p.E318K variant in a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC. All tumors displayed the MITF variant and were characterized by amplification of chromosomes 7 and 17, hallmarks of type 1 papillary RCC. We demonstrated that MITF p.E318K variant results in altered transcriptional activity and that downstream targets of MiT family members, such as GPNMB, are dysregulated in the tumors. Association of the pathogenic MITF variant with bilateral and multifocal type 1 papillary RCC in this family supports its role as a risk allele for the development of RCC and emphasizes the importance of screening for MITF variants irrelevant of the RCC histologic subtype. This study identifies potential biomarkers for the disease, such as GPNMB expression, that may facilitate the development of targeted therapies for patients affected with MITF-associated RCC.

Analysis of clinical characteristics of a pedigree with familial renal cell carcinoma and germline mutation of VHL gene

To detect germline mutation in a pedigree affected with familial renal cell carcinoma and explore its molecular pathogenesis. Peripheral blood samples from the patients and her family members were collected for the extraction of genomic DNA. Sanger sequencing, real-time quantitative PCR and reverse transcriptase-PCR (RT-PCR) were carried out to detect single base mutation, small insertion and deletion, and large fragment deletion of the VHL gene. Real-time quantitative PCR combined with sequencing of RT-PCR product showed that there was a single-copy deletional germline mutation in exon 2 of the VHL gene in the proband. Loss of heterozygosity in exon 2 of the VHL gene probably underlay the etiology of familial renal cell carcinoma in this pedigree. Screening for germline mutations of the VHL gene can effectively predict the prognosis of individual patients.

Ten-year outcomes of renal tumor radiofrequency ablation

PurposeWe sought to review long-term oncological outcomes of patients with renal tumors treated with radiofrequency ablation (RFA) greater than 10 years ago. Materials and MethodsPatients with renal tumors that underwent RFA from November 2000 to August 2007 were reviewed retrospectively. Demographic, clinical, and radiologic data were assessed to determine evidence for recurrence of disease. Patients with familial renal cell carcinoma syndromes were excluded from the study. Disease-free survival (DFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) were calculated with the Kaplan-Meier method. Subgroup analysis of patients that had at least 10 years follow-up was performed to determine actual 10-year survival. Analysis was also performed based on tumor size. ResultsA total of 112 tumors in 106 patients underwent RFA. Median follow-up was 79 months (IQR 28.9 – 121.1) and mean tumor size was 2.5 cm (SD ± 0.8). Initial technical success was achieved in 97% of cases. There were 10 recurrences. Kaplan-Meier six-year disease-free survival and cancer-specific survival was 89% and 96%, respectively. DFS drops to 68% for tumors greater than 3cm. Within the subgroup that had at least 10-year follow-up, actual DFS, CSS, and OS were 82%, 94%, and 49%, respectively. No patient recurred after 5 years. ConclusionsRFA is a safe and effective treatment option for small renal masses less than 3 cm in diameter. We report good oncologic outcomes with actual 10-year survival data. No recurrences occurred after 5 years. Tumors greater than 3cm have significantly poorer outcomes.

Atypical tuberous sclerosis complex presenting as familial renal cell carcinoma with leiomyomatous stroma

We report an atypical tuberous sclerosis complex (TSC) phenotype presenting as familial multiple renal cell carcinomas (RCCs) with (angio)leiomyomatous stroma (RCCLS) (5/7 familial RCCs) on a background of multiple angiomyolipomas, hypopigmented skin macules, and absence of neurological anomalies. In the index case and three relatives, germline genetic testing identified a heterozygous TSC2 missense pathogenic variant [c.2714 G > A, (p.Arg905Gln)], a rare TSC‐associated alteration which has previously been associated with a milder TSC phenotype. Whole‐exome sequencing of five RCCs from the index case and one RCC from his mother demonstrated either unique tumour‐specific deleterious second hits in TSC2 or significant allelic imbalance at the TSC2 gene locus (5/6 RCCs). This study confirms the key tumourigenic role of tumour‐specific TSC2 second hits in TSC‐associated RCCs and supports the notion that RCCLS may be strongly related to abnormalities of the mTOR pathway.

BAP1 tumor predisposition syndrome: Preliminary data from a laboratory-based multigene panel testing cohort.

490 Background: Germline mutations in BAP1 have recently been shown to cause a tumor predisposition syndrome characterized by renal cell carcinoma (RCC), uveal melanoma, cutaneous melanoma, and mesothelioma. However, mutations have thus far been identified in highly enriched cohorts and the tumor spectrum among individuals with a broader phenotype undergoing multi-gene panel testing (MGPT) has not been described. Other genes associated with familial RCC have been established, such as FLCN (Birt-Hogg Dube syndrome) and VHL (von Hippel Lindau), but the proportion of BAP1 mutations in individuals with RCC is not yet known. Here we aim to describe the clinical features of individuals with BAP1 mutations identified from a clinical laboratory cohort, and to estimate the frequency of BAP1 mutations in individuals with kidney cancer. Methods: Since May 2015, a total of 6956 tests have been ordered that include BAP1 at our diagnostic laboratory. Retrospective data review yielded molecular and clinical details for individuals with identified mutations. Results: Thirteen individuals with BAP1 mutations have been identified. Cancer diagnoses in probands and family members consist of breast cancer (reported in 69.2% of kindreds), RCC (61.5%), melanoma (61.5%), mesothelioma (46.2%), lung cancer (46.2%), non-melanoma skin cancer (30.8%), and cholangiocarcinoma (15.4%). Among probands with kidney cancer undergoing MGPT (n = 1012), there is no difference in mutation rate of BAP1 compared to VHL (n = 3; OR 2.01 p = 0.51) or FLCN (n = 10; OR 0.598 p = 0.45). Conclusions: Cancer histories in our laboratory-selected cohort of BAP1 mutation carriers are consistent with those reported in the clinical literature, lending credence to the notion that BAP1 tumor predisposition syndrome is highly penetrant and consists of a constellation of several core cancers. The observation of breast, lung, non-melanoma skin cancer, and cholangiocarcinoma has also been reported in the literature and warrants further study. Our results suggest that BAP1 mutations are found at a similar frequency as other well-known kidney cancer genes, supporting its position as an important differential when considering genetic testing for RCC.

Validation of a Postoperative Nomogram Predicting Recurrence in Patients with Conventional Clear Cell Renal Cell Carcinoma

BackgroundClear cell renal cell carcinoma (RCC) continues to be the most commonly diagnosed subtype and is associated with more aggressive behavior than papillary and chromophobe RCC. Predicting disease recurrence after surgical extirpation is important for counseling and targeting those at high risk for adjuvant therapy clinical trials. ObjectiveTo validate a postoperative nomogram predicting 5-yr recurrence-free probability (RFP) for clinically localized clear cell RCC. Design, setting, and participantsWe identified all patients who underwent nephrectomy for clinically localized clear cell RCC from 1990 to 2009 at Memorial Sloan Kettering Cancer Center. After excluding patients with bilateral renal masses, familial RCC syndromes, and T3c or T4 tumors due to the limited number, 1642 participants were available for analysis. InterventionsPartial or radical nephrectomy. Outcome measurements and statistical analysisDisease recurrence was defined as any new tumor after nephrectomy or kidney cancer–specific mortality, whichever occurred first. A postoperative nomogram was used to calculate the predicted 5-yr RFP, and these values were compared with the actual 5-yr RFP. Nomogram performance was evaluated by concordance index and calibration plot. Results and limitationsMedian follow-up was 39 mo (interquartile range: 14–79 mo), and disease recurrence was observed in 50 patients. The nomogram concordance index was 0.81. The calibration curve showed that the nomogram underestimated the actual 5-yr RFP. We updated the nomogram by including the entire patient population, which maintained performance and significantly improved calibration. ConclusionsThe updated clear cell RCC postoperative nomogram performed well in the combined cohort. Underestimation of actual 5-yr RFP by the original nomogram may be due to increased surgeon experience and other unknown variables. Patient summaryWe updated a valuable prediction tool used for assessing the disease recurrence probability after nephrectomy for clear cell renal cell carcinoma.

Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma.

Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC. Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Can Mutations in the BAP1 Gene be Detected by Immunohisto-chemistry in Hereditary Kidney Cancers?

Background: Hereditary renal cell carcinoma (RCC) constitutes about 5% of all RCCs. The most common and well studied syndromes include, VHL, HLRCC, BHD, Familial Oncocytoma, RCC Papillary Type 1, TSC, RCC associated with Succinate dehydrogenase B (SHDB) mutations and others. Several genes, including VHL, MET, FLCN, FH and genes encoding the succinate dehydrogenase (SDH) subunits B/C/D have been identified as causative. However, the genetic basis of a significant percentage of familial RCC, some with clear cell morphology remain unknown. BAP1 (BRCA1 associated protein-1), a tumor suppressor gene that encodes a nuclear deubiquitinase, is inactivated in 15% of sporadic clear cell RCCs and its loss was associated with high tumor grade and poor prognosis. In this study, we investigated the possible role of this gene in the spectrum of RCC part of hereditary syndromes. Materials and Methods: To elucidate the role of BAP1 in all the spectrum of hereditary RCC, we studied by IHC a panel of RCCs which covers the spectrum of kidney cancers and included 10 VHL tumors, 6 HLRCCs, 8 chromophobe, 5 Hereditary Papillary Type 1, 6 Oncocytomas, 3 BHD (hybrid), and 24 sporadic clear cell RCCs. To analyze the BAP1 expression in these tumors, formalin fixed paraffin embedded (FFPE) tissues were immunostained with mouse monoclonal anti-human BAP1 antibody (Clone C-4, Santa Cruz). Results: We found that all the tumors except two showed positive nuclear staining for BAP1. The two negative cases that were negative for BAP1 were Clear cell type and belonged to two siblings. Molecular analysis in a prepublished study showed both patients harboring the p.L14H mutation. Conclusion: Our study supports the hypothesis that BAP1 mutations can play a role in hereditary syndromes predominantly in clear cell tumors. Staining for BAP1 should be done when there is no definite known mutation in a clear cell cancer but the patient gives history of familial kidney cancer. The two related patients who had similar mutations had aggressive, metastatic disease, which suggests that probably BAP1 does play a role in hereditary RCC clear cell type.

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.

Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene. BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.

Germline PTEN Mutation Cowden Syndrome: An Underappreciated Form of Hereditary Kidney Cancer

Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Functional significance of erythropoietin in renal cell carcinoma

One of the molecules regulated by the transcription factor, hypoxia inducible factor (HIF), is the hypoxia-responsive hematopoietic factor, erythropoietin (EPO). This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC. VHL mutations up-regulate and stabilize HIF, which in turn activates many downstream molecules, including EPO, that are known to promote angiogenesis, drug resistance, proliferation and progression of solid tumours. HIFs typically respond to hypoxic cellular environment. While the hypoxic microenvironment plays a critical role in the development and progression of tumours in general, it is of special significance in the case of RCC because of the link between VHL, HIF and EPO. EPO and its receptor, EPOR, are expressed in many cancers, including RCC. This limits the use of recombinant human EPO (rhEPO) to treat anaemia in cancer patients, because the rhEPO may be stimulatory to the cancer. EPO may also stimulate epithelial-mesenchymal transition (EMT) in RCC, and pathological EMT has a key role in cancer progression. In this mini review, we summarize the current knowledge of the role of EPO in RCC. The available data, either for or against the use of EPO in RCC patients, are equivocal and insufficient to draw a definitive conclusion.