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The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
Integrative clinical and molecular characterization of translocation renal cell carcinoma
Ziad Bakouny1, Ananthan Sadagopan2, Praful Ravi2
1Department 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.
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.
Insights
Translocation renal cell carcinoma (tRCC) is a kidney cancer subtype characterized by MiT/TFE gene fusions. This study reveals tRCC exhibits an NRF2-driven antioxidant response, impacting treatment outcomes and suggesting immune checkpoint inhibitors may be more effective than VEGFR-TKIs.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Translocation renal cell carcinoma (tRCC) is a rare kidney cancer subtype.
- It is driven by MiT/TFE gene fusions, but its molecular and clinical features remain poorly understood.
Purpose of the Study:
- To comprehensively define the clinical and molecular landscape of tRCC.
- To identify therapeutic vulnerabilities and potential treatment strategies for tRCC patients.
Main Methods:
- Integrative analysis of genomic, clinical trial, and retrospective data from 152 tRCC patients.
- Transcriptional profiling to identify key molecular pathways.
- Multiparametric immunofluorescence to characterize tumor immune microenvironment.
Main Results:
- tRCC is characterized by MiT/TFE fusions and frequent 9p21.3 deletions.
- A heightened NRF2-driven antioxidant response is observed, correlating with resistance to targeted therapies.
- Patients treated with immune checkpoint inhibitors (ICI) showed better outcomes than those treated with VEGFR-TKIs.
- Tumors are infiltrated by CD8+ T cells with an exhausted immunophenotype distinct from clear cell RCC.
Conclusions:
- This study provides a comprehensive definition of tRCC's clinical and molecular features.
- The findings highlight the role of NRF2 in tRCC pathogenesis and treatment resistance.
- The distinct immune microenvironment and differential treatment responses suggest novel therapeutic avenues for tRCC.
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