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.
Cell reports. 2022 Jan 04 [Epub]
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
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., Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA., 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., Harvard Medical School, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Harvard Medical School, Boston, MA, USA; Department of Internal Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA., 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., Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA., Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA., Division of Medical Oncology/Hematology, William Osler Health System, Brampton, ON, Canada., Division of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada., Division of Urology, Brigham and Women's Hospital, Boston, MA, USA., Department of Thoracic/Head and Neck Medical Oncology, Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA., 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; Division of Urology, Brigham and Women's Hospital, Boston, MA, USA., Department of Urology, Massachusetts General Hospital, Boston, MA, USA., 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., Beth Israel Deaconess Medical Center, Boston, MA, USA., Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA., 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: ., 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: .