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Updated Recommendations on the Diagnosis, Management, and Clinical Trial Eligibility Criteria for Patients With Renal Medullary Carcinoma.
Msaouel P, Hong AL, Mullen EA, Atkins MB, Walker CL, Lee CH, Carden MA, Genovese G, Linehan WM, Rao P, Merino MJ, Grodman H, Dome JS, Fernandez CV, Geller JI, Apolo AB, Daw NC, Hodges HC, Moxey-Mims M, Wei D, Bottaro DP, Staehler M, Karam JA, Rathmell WK, Tannir NM
(2019) Clin Genitourin Cancer 17: 1-6
MeSH Terms: Carcinoma, Medullary, Carcinoma, Renal Cell, Clinical Trials as Topic, Databases, Factual, Eligibility Determination, Humans, Kidney Neoplasms, Patient Selection, Practice Guidelines as Topic, Prognosis
Show Abstract · Added October 30, 2019
Renal medullary carcinoma (RMC) is one of the most aggressive renal cell carcinomas. It predominantly afflicts young adults and adolescents with sickle cell trait and other sickle hemoglobinopathies, and is refractory to targeted and antiangiogenic therapies used in patients with clear-cell renal cell carcinoma. Platinum-based cytotoxic chemotherapy is the mainstay for RMC treatment. On the basis of recent advances in the diagnosis, management, and clinical trial development for RMC, a panel of experts met in October 2017 and developed updated consensus recommendations to inform clinicians, researchers, and patients. Because RMC often aggressively recurs while patients are still recovering from nephrectomy, upfront chemotherapy should be considered for most patients, including those with localized disease. After safety and dosing information has been established in adults, phase II and III trials enrolling patients with RMC should allow patients aged 12 years and older to be accrued. Patients with the very rare unclassified renal cell carcinoma with medullary phenotype variant should be included in RMC trials. Medical providers should be aware that RMC can afflict subjects of all races, and not only those of African descent, and that the presence of sickle cell trait, or of other sickle hemoglobinopathies, can affect drug responses and toxicity.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma.
Smith CC, Beckermann KE, Bortone DS, De Cubas AA, Bixby LM, Lee SJ, Panda A, Ganesan S, Bhanot G, Wallen EM, Milowsky MI, Kim WY, Rathmell WK, Swanstrom R, Parker JS, Serody JS, Selitsky SR, Vincent BG
(2018) J Clin Invest 128: 4804-4820
MeSH Terms: Carcinoma, Renal Cell, Endogenous Retroviruses, Humans, Immunotherapy, Kidney Neoplasms, Prognosis, Tumor Microenvironment
Show Abstract · Added October 30, 2019
Human endogenous retroviruses (hERVs) are remnants of exogenous retroviruses that have integrated into the genome throughout evolution. We developed a computational workflow, hervQuant, which identified more than 3,000 transcriptionally active hERVs within The Cancer Genome Atlas (TCGA) pan-cancer RNA-Seq database. hERV expression was associated with clinical prognosis in several tumor types, most significantly clear cell renal cell carcinoma (ccRCC). We explored two mechanisms by which hERV expression may influence the tumor immune microenvironment in ccRCC: (i) RIG-I-like signaling and (ii) retroviral antigen activation of adaptive immunity. We demonstrated the ability of hERV signatures associated with these immune mechanisms to predict patient survival in ccRCC, independent of clinical staging and molecular subtyping. We identified potential tumor-specific hERV epitopes with evidence of translational activity through the use of a ccRCC ribosome profiling (Ribo-Seq) dataset, validated their ability to bind HLA in vitro, and identified the presence of MHC tetramer-positive T cells against predicted epitopes. hERV sequences identified through this screening approach were significantly more highly expressed in ccRCC tumors responsive to treatment with programmed death receptor 1 (PD-1) inhibition. hervQuant provides insights into the role of hERVs within the tumor immune microenvironment, as well as evidence that hERV expression could serve as a biomarker for patient prognosis and response to immunotherapy.
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Epigenetic modifiers: activities in renal cell carcinoma.
de Cubas AA, Rathmell WK
(2018) Nat Rev Urol 15: 599-614
MeSH Terms: Carcinoma, Renal Cell, Chromatin, Epigenesis, Genetic, Humans, Kidney Neoplasms, Mutation
Show Abstract · Added October 30, 2019
Renal cell carcinomas (RCCs) are a diverse set of malignancies that have recently been shown to harbour mutations in a number of chromatin modifier genes - including PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2 - through high-throughput sequencing efforts. Current research focuses on understanding the biological activities that chromatin modifiers employ to suppress tumorigenesis and on developing clinical approaches that take advantage of this knowledge. Unsurprisingly, several common themes unify the functions of these epigenetic modifiers, particularly regulation of histone post-translational modifications and nucleosome organization. Furthermore, chromatin modifiers also govern processes crucial for DNA repair and maintenance of genomic integrity as well as the regulation of splicing and other key processes. Many chromatin modifiers have additional non-canonical roles in cytoskeletal regulation, which further contribute to genomic stability, expanding the repertoire of functions that might be essential in tumorigenesis. Our understanding of how mutations in chromatin modifiers contribute to tumorigenesis in RCC is improving but remains an area of intense investigation. Importantly, elucidating the activities of chromatin modifiers offers intriguing opportunities for the development of new therapeutic interventions in RCC.
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VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.
Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, Liu XD, Jonasch E, Xie L, Chen X, Yao X, Teh BT, Tan P, Zheng X, Li M, Lawrence C, Fan J, Geng J, Liu X, Hu L, Wang J, Liao C, Hong K, Zurlo G, Parker JS, Auman JT, Perou CM, Rathmell WK, Kim WY, Kirschner MW, Kaelin WG, Baldwin AS, Zhang Q
(2018) Science 361: 290-295
MeSH Terms: Animals, Carcinoma, Renal Cell, Chromatin Immunoprecipitation, Female, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Hydroxylation, Kidney Neoplasms, Mice, Mice, SCID, Molecular Targeted Therapy, Mutation, NF-kappa B, Oncogenes, Substrate Specificity, Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added October 30, 2019
Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.
McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, Fong L, Joseph RW, Pal SK, Reeves JA, Sznol M, Hainsworth J, Rathmell WK, Stadler WM, Hutson T, Gore ME, Ravaud A, Bracarda S, Suárez C, Danielli R, Gruenwald V, Choueiri TK, Nickles D, Jhunjhunwala S, Piault-Louis E, Thobhani A, Qiu J, Chen DS, Hegde PS, Schiff C, Fine GD, Powles T
(2018) Nat Med 24: 749-757
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carcinoma, Renal Cell, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Kidney Neoplasms, Male, Middle Aged, Mutation, Sunitinib, Treatment Outcome
Show Abstract · Added October 30, 2019
We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
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Integrative radiomics expression predicts molecular subtypes of primary clear cell renal cell carcinoma.
Yin Q, Hung SC, Rathmell WK, Shen L, Wang L, Lin W, Fielding JR, Khandani AH, Woods ME, Milowsky MI, Brooks SA, Wallen EM, Shen D
(2018) Clin Radiol 73: 782-791
MeSH Terms: Biomarkers, Tumor, Carcinoma, Renal Cell, Contrast Media, Humans, Imaging, Three-Dimensional, Kidney Neoplasms, Magnetic Resonance Imaging, Multimodal Imaging, Neoplasm Grading, Neoplasm Staging, Positron-Emission Tomography, Retrospective Studies
Show Abstract · Added October 30, 2019
AIM - To identify combined positron-emission tomography (PET)/magnetic resonance imaging (MRI)-based radiomics as a surrogate biomarker of intratumour disease risk for molecular subtype ccA and ccB in patients with primary clear cell renal cell carcinoma (ccRCC).
MATERIALS AND METHODS - PET/MRI data were analysed retrospectively from eight patients. One hundred and sixty-eight radiomics features for each tumour sampling based on the regionally sampled tumours with 23 specimens were extracted. Sparse partial least squares discriminant analysis (SPLS-DA) was applied to feature screening on high-throughput radiomics features and project the selected features to low-dimensional intrinsic latent components as radiomics signatures. In addition, multilevel omics datasets were leveraged to explore the complementing information and elevate the discriminative ability.
RESULTS - The correct classification rate (CCR) for molecular subtype classification by SPLS-DA using only radiomics features was 86.96% with permutation test p=7×10. When multi-omics datasets including mRNA, microvascular density, and clinical parameters from each specimen were combined with radiomics features to refine the model of SPLS-DA, the best CCR was 95.65% with permutation test, p<10; however, even in the case of generating the classification based on transcription features, which is the reference standard, there is roughly 10% classification ambiguity. Thus, this classification level (86.96-95.65%) of the proposed method represents the discriminating level that is consistent with reality.
CONCLUSION - Featured with high accuracy, an integrated multi-omics model of PET/MRI-based radiomics could be the first non-invasive investigation for disease risk stratification and guidance of treatment in patients with primary ccRCC.
Published by Elsevier Ltd.
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Haploinsufficiency for Microtubule Methylation Is an Early Driver of Genomic Instability in Renal Cell Carcinoma.
Chiang YC, Park IY, Terzo EA, Tripathi DN, Mason FM, Fahey CC, Karki M, Shuster CB, Sohn BH, Chowdhury P, Powell RT, Ohi R, Tsai YS, de Cubas AA, Khan A, Davis IJ, Strahl BD, Parker JS, Dere R, Walker CL, Rathmell WK
(2018) Cancer Res 78: 3135-3146
MeSH Terms: Animals, Carcinogenesis, Carcinoma, Renal Cell, Cell Line, Tumor, Chromosomes, Human, Pair 3, Fibroblasts, Gene Knockdown Techniques, Genomic Instability, Haploinsufficiency, Histone-Lysine N-Methyltransferase, Histones, Humans, Kidney Neoplasms, Kidney Tubules, Proximal, Lysine, Methylation, Mice, Micronuclei, Chromosome-Defective, Microtubules
Show Abstract · Added October 30, 2019
Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase , which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that monoallelic, -deficient cells retaining H3K36me3, but not αTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In -inactivated human kidney cells, rescue with a pathogenic mutant deficient for microtubule (αTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability. Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis. .
©2018 American Association for Cancer Research.
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Phase II Study of Two Weeks on, One Week off Sunitinib Scheduling in Patients With Metastatic Renal Cell Carcinoma.
Jonasch E, Slack RS, Geynisman DM, Hasanov E, Milowsky MI, Rathmell WK, Stovall S, Juarez D, Gilchrist TR, Pruitt L, Ornstein MC, Plimack ER, Tannir NM, Rini BI
(2018) J Clin Oncol 36: 1588-1593
MeSH Terms: Administration, Oral, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Renal Cell, Drug Administration Schedule, Female, Humans, Kidney Neoplasms, Male, Middle Aged, Sunitinib, Surveys and Questionnaires, Treatment Outcome
Show Abstract · Added October 30, 2019
Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy-General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.
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The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.
Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, Bowlby R, Gibb EA, Akbani R, Beroukhim R, Bottaro DP, Choueiri TK, Gibbs RA, Godwin AK, Haake S, Hakimi AA, Henske EP, Hsieh JJ, Ho TH, Kanchi RS, Krishnan B, Kwiatkowski DJ, Lui W, Merino MJ, Mills GB, Myers J, Nickerson ML, Reuter VE, Schmidt LS, Shelley CS, Shen H, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Vincent BG, Vocke CD, Wheeler DA, Yang L, Kim WY, Robertson AG, Cancer Genome Atlas Research Network, Spellman PT, Rathmell WK, Linehan WM
(2018) Cell Rep 23: 313-326.e5
MeSH Terms: Biomarkers, Tumor, Carcinoma, Renal Cell, Cyclin-Dependent Kinase Inhibitor p16, Genome, Human, Humans, Kidney Neoplasms, Metabolic Networks and Pathways, Nuclear Proteins, PTEN Phosphohydrolase, Phenotype, Survival Analysis, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase
Show Abstract · Added October 30, 2019
Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.
Published by Elsevier Inc.
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The Clinical Presentation, Survival Outcomes, and Management of Patients With Renal Cell Carcinoma and Cardiac Metastasis Without Inferior Vena Cava Involvement: Results From a Pooled Clinical Trial Database and Systematic Review of Reported Cases.
Viteri Malone MA, Ares GR, De Velasco G, Brandão R, Lin X, Norton C, Simantov R, Moslehi J, Krajewski KM, Choueiri TK, McKay RR
(2018) Clin Genitourin Cancer 16: e327-e333
MeSH Terms: Adult, Aged, Carcinoma, Renal Cell, Clinical Trials as Topic, Female, Heart Neoplasms, Humans, Kidney Neoplasms, Male, Middle Aged, Molecular Targeted Therapy, Progression-Free Survival, Retrospective Studies, Survival Analysis, Treatment Outcome, Vena Cava, Inferior
Show Abstract · Added April 22, 2018
BACKGROUND - Cardiac metastases from renal cell carcinoma (RCC) are uncommon and there are limited data regarding the presentation and outcomes of this population. The objective of this study was to evaluate the characteristics and outcomes of patients with RCC with cardiac metastasis without inferior vena cava (IVC) involvement.
MATERIALS AND METHODS - We conducted a pooled retrospective analysis of metastatic RCC patients treated in 4 clinical trials. Additionally, we conducted a systematic review of cases reported in the literature from 1973 to 2015. Patients with cardiac metastases from RCC without IVC involvement were included. Patient and disease characteristics were described. Additionally, treatments, response to therapy, and survival outcomes were summarized.
RESULTS - Of 1765 metastatic RCC patients in the clinical trials database, 10 had cardiac metastases without IVC involvement. All patients received treatment with targeted therapy. There was 1 observed partial response (10%) and 6 patients showed stable disease (60%). The median progression-free survival was 6.9 months. The systematic review of reported clinical cases included 39 patients. In these patients, the most common cardiac site of involvement was the right ventricle (51%; n = 20). Patients were treated with medical (28%; n = 11) and/or surgical treatment (49%; n = 19) depending on whether disease was isolated (n = 13) or multifocal (n = 26).
CONCLUSION - To our knowledge, this is the first series to report on the presentation and outcomes of patients with cardiac metastasis without IVC involvement in RCC. We highlight that although the frequency of patients with cardiac metastases without IVC involvement is low, these patients have a unique clinical presentation and warrant special multidisciplinary management.
Copyright © 2017 Elsevier Inc. All rights reserved.
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16 MeSH Terms