Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma

Ziad Bakouny, Ananthan Sadagopan, Praful Ravi, Nebiyou Y. Metaferia, Jiao Li, Shatha AbuHammad, Stephen Tang, Thomas Denize, Emma R. Garner, Xin Gao, David A. Braun, Laure Hirsch, John A. Steinharter, Gabrielle Bouchard, Emily Walton, Destiny West, Chris Labaki, Shaan Dudani, Chun-Loo Gan, Vidyalakshmi Sethunath, Filipe LF. Carvalho, Alma Imamovic, Cora Ricker, Natalie I. Vokes, Jackson Nyman, Jihye Park, Michelle S. Hirsch, Rizwan Haq, Gwo-Shu Mary Lee, Bradley A. McGregor, Steven L. Chang, Adam S. Feldman, Catherine J. Wu, David F. McDermott, Daniel Y.C. Heng, Sabina Signoretti, Eliezer M. Van Allen, Toni K. Choueiri, Srinivas R. Viswanathan
doi: https://doi.org/10.1101/2021.04.14.439908
Ziad Bakouny
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ananthan Sadagopan
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Praful Ravi
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nebiyou Y. Metaferia
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jiao Li
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shatha AbuHammad
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen Tang
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Denize
3Harvard Medical School, Boston, MA, USA
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emma R. Garner
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xin Gao
3Harvard Medical School, Boston, MA, USA
5Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David A. Braun
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laure Hirsch
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
3Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John A. Steinharter
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gabrielle Bouchard
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emily Walton
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Destiny West
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chris Labaki
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shaan Dudani
6Division of Medical Oncology/Hematology, William Osler Health System, Brampton, ON, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Chun-Loo Gan
7Division of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, AB, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vidyalakshmi Sethunath
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Filipe LF. Carvalho
8Division of Urology, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alma Imamovic
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Cora Ricker
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Natalie I. Vokes
9Department of Thoracic/Head and Neck Medical Oncology; Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jackson Nyman
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jihye Park
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle S. Hirsch
3Harvard Medical School, Boston, MA, USA
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rizwan Haq
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gwo-Shu Mary Lee
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bradley A. McGregor
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven L. Chang
8Division of Urology, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adam S. Feldman
10Department of Urology, Massachusetts General Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Catherine J. Wu
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
11Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David F. McDermott
12Beth Israel Deaconess Medical Center, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel Y.C. Heng
7Division of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, AB, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sabina Signoretti
4Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
13Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eliezer M. Van Allen
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Toni K. Choueiri
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
3Harvard Medical School, Boston, MA, USA
11Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: toni_choueiri@dfci.harvard.edu srinivas.viswanathan@dfci.harvard.edu
Srinivas R. Viswanathan
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Harvard Medical School, Boston, MA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: toni_choueiri@dfci.harvard.edu srinivas.viswanathan@dfci.harvard.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

ABSTRACT

Translocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 tRCC patients identified across multiple genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8 + tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

Competing Interest Statement

The following authors report competing interests (all outside of the submitted work): Z.B.: Research funding from Bristol-Myers Squibb … Genentech/imCORE; Honoraria from UpToDate. X.G.: Advisory board for Exelixis. D.A.B.: Nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis, and consulting/personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. N.I.V.: Advisory board to Sanofi/Genzyme. M.S.H.: Consultant, Janssen Pharmaceuticals; UpToDate. R.H.: Research funding from Novartis. B.A.M.: Consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, Dendreon, Bristol Myers Squibb, Calithera, and EMD Serono. Research funding to the institution from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. A.S.F.: Olympus America, Inc (Consultant); Roche, Janssen (Honoraria); Vessi Medical (Advisory Board). C.J.W.: Equity holder of BioNTech, Inc; Research funding from Pharmacyclics. D.F.M.: Honoraria from BMS, Pfizer, Merck, Alkermes, Inc., EMD Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Therapeutics, and Calithera Biosciences; Research Support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, Inc. D.Y.C.H.: Consultancies and research funding from Pfizer, Novartis, BMS, Merck, Eisai, Ipsen, Exelixis. S.S.: Grants from Exelixis, grants from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from CRISPR Therapeutics, personal fees from NCI, and personal fees from AACR; a patent for Biogenex with royalties paid. E.M.V.A.: Advisory/Consulting: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation. T.K.C.: Research (Institutional and personal): Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon; Consulting/honoraria or Advisory Role: Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, Up-to-Date. CME-related events (e.g.: OncLive, PVI, MJH Life Sciences). NCI GU Steering Committee; Stock ownership: Pionyr, Tempest; Patents filed, royalties or other intellectual properties: related to biomarkers of immune checkpoint blockers and ctDNA; Travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; No speaker bureau. S.R.V.: Consulting, MPM Capital and Vida Ventures. Spouse is an employee of and holds equity in Kojin Therapeutics. J.L. … S.R.V: institutional patent application on targets in tRCC. All other authors report no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted April 15, 2021.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma
Ziad Bakouny, Ananthan Sadagopan, Praful Ravi, Nebiyou Y. Metaferia, Jiao Li, Shatha AbuHammad, Stephen Tang, Thomas Denize, Emma R. Garner, Xin Gao, David A. Braun, Laure Hirsch, John A. Steinharter, Gabrielle Bouchard, Emily Walton, Destiny West, Chris Labaki, Shaan Dudani, Chun-Loo Gan, Vidyalakshmi Sethunath, Filipe LF. Carvalho, Alma Imamovic, Cora Ricker, Natalie I. Vokes, Jackson Nyman, Jihye Park, Michelle S. Hirsch, Rizwan Haq, Gwo-Shu Mary Lee, Bradley A. McGregor, Steven L. Chang, Adam S. Feldman, Catherine J. Wu, David F. McDermott, Daniel Y.C. Heng, Sabina Signoretti, Eliezer M. Van Allen, Toni K. Choueiri, Srinivas R. Viswanathan
bioRxiv 2021.04.14.439908; doi: https://doi.org/10.1101/2021.04.14.439908
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma
Ziad Bakouny, Ananthan Sadagopan, Praful Ravi, Nebiyou Y. Metaferia, Jiao Li, Shatha AbuHammad, Stephen Tang, Thomas Denize, Emma R. Garner, Xin Gao, David A. Braun, Laure Hirsch, John A. Steinharter, Gabrielle Bouchard, Emily Walton, Destiny West, Chris Labaki, Shaan Dudani, Chun-Loo Gan, Vidyalakshmi Sethunath, Filipe LF. Carvalho, Alma Imamovic, Cora Ricker, Natalie I. Vokes, Jackson Nyman, Jihye Park, Michelle S. Hirsch, Rizwan Haq, Gwo-Shu Mary Lee, Bradley A. McGregor, Steven L. Chang, Adam S. Feldman, Catherine J. Wu, David F. McDermott, Daniel Y.C. Heng, Sabina Signoretti, Eliezer M. Van Allen, Toni K. Choueiri, Srinivas R. Viswanathan
bioRxiv 2021.04.14.439908; doi: https://doi.org/10.1101/2021.04.14.439908

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4369)
  • Biochemistry (9546)
  • Bioengineering (7068)
  • Bioinformatics (24768)
  • Biophysics (12560)
  • Cancer Biology (9924)
  • Cell Biology (14297)
  • Clinical Trials (138)
  • Developmental Biology (7930)
  • Ecology (12074)
  • Epidemiology (2067)
  • Evolutionary Biology (15954)
  • Genetics (10904)
  • Genomics (14706)
  • Immunology (9844)
  • Microbiology (23582)
  • Molecular Biology (9454)
  • Neuroscience (50691)
  • Paleontology (369)
  • Pathology (1535)
  • Pharmacology and Toxicology (2674)
  • Physiology (3997)
  • Plant Biology (8639)
  • Scientific Communication and Education (1505)
  • Synthetic Biology (2388)
  • Systems Biology (6415)
  • Zoology (1344)