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.

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