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 L F Carvalho; Alma Imamovic; Cora Ricker; Natalie I Vokes; Jackson Nyman; Jacob E Berchuck; 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:10.1016/j.celrep.2021.110190

Integrative clinical and molecular characterization of translocation renal cell carcinoma

Cell Rep. 2022 Jan 4;38(1):110190. doi: 10.1016/j.celrep.2021.110190.

Authors

Ziad Bakouny¹, Ananthan Sadagopan², Praful Ravi², Nebiyou Y Metaferia², Jiao Li², Shatha AbuHammad³, Stephen Tang², Thomas Denize⁴, Emma R Garner², Xin Gao⁵, David A Braun⁶, Laure Hirsch⁷, John A Steinharter², Gabrielle Bouchard², Emily Walton⁸, Destiny West⁸, Chris Labaki², Shaan Dudani⁹, Chun-Loo Gan¹⁰, Vidyalakshmi Sethunath², Filipe L F Carvalho¹¹, Alma Imamovic², Cora Ricker², Natalie I Vokes¹², Jackson Nyman², Jacob E Berchuck², Jihye Park¹³, Michelle S Hirsch⁴, Rizwan Haq³, Gwo-Shu Mary Lee², Bradley A McGregor², Steven L Chang¹⁴, Adam S Feldman¹⁵, Catherine J Wu¹⁶, David F McDermott¹⁷, Daniel Y C Heng¹⁰, Sabina Signoretti¹⁸, Eliezer M Van Allen³, Toni K Choueiri¹⁹, Srinivas R Viswanathan²⁰

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Harvard Medical School, Boston, MA, USA; Department of Internal Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Yale Cancer Center / Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA.
⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁹ Division of Medical Oncology/Hematology, William Osler Health System, Brampton, ON, Canada.
¹⁰ Division of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada.
¹¹ Division of Urology, Brigham and Women's Hospital, Boston, MA, USA.
¹² Department of Thoracic/Head and Neck Medical Oncology, Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Harvard Medical School, Boston, MA, USA; Division of Urology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁵ Department of Urology, Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: toni_choueiri@dfci.harvard.edu.
²⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: srinivas.viswanathan@dfci.harvard.edu.

Abstract

Translocation renal cell carcinoma (tRCC) is a 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 patients with tRCC identified across 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 targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8⁺ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

Keywords: MITF; NRF2; TFE3; TFEB; VEGFR; genomics; immune checkpoint inhibition; immunotherapy; oxidative stress; translocation renal cell carcinoma.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
CD8-Positive T-Lymphocytes / immunology
Carcinoma, Renal Cell / drug therapy
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / pathology
Gene Expression Regulation, Neoplastic
Gene Fusion / genetics
Humans
Immune Checkpoint Inhibitors / therapeutic use
Kidney Neoplasms / drug therapy
Kidney Neoplasms / genetics*
Kidney Neoplasms / pathology
Microphthalmia-Associated Transcription Factor / genetics*
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
Protein Kinase Inhibitors / therapeutic use
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Biomarkers, Tumor
Immune Checkpoint Inhibitors
MITF protein, human
Microphthalmia-Associated Transcription Factor
Oncogene Proteins, Fusion
Protein Kinase Inhibitors
TFE3 protein, human
FLT1 protein, human
Vascular Endothelial Growth Factor Receptor-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding