Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma: A Comparative Study With Papillary and Clear Cell Renal Cell Carcinomas

Shuanzeng Wei, Harris B. Krause, Daniel M. Geynisman, Andrew Elliott, Alexander Kutikov, Robert G. Uzzo, Jianming Pei, Pedro Barata, Benedito Carneiro, Elisabeth Heath, Charles Ryan, Alex Farrell, Chadi Nabhan, Rouba Ali-Fehmi, Abdul Rafeh Naqash, Pedram Argani, Rana R. McKay

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1 Scopus citations

Abstract

TFE3-rearranged renal cell carcinoma (rRCC) is a rare subtype of renal cell carcinomas belonging to the MiT family translocation RCC. To further elucidate the co-alterations that occur along with TFE3 fusions in rRCC, we characterized the genomic, transcriptional, and immune landscapes in comparison to clear cell (ccRCC) and papillary renal cell carcinoma (pRCC). Next-generation sequencing of RNA (whole transcriptome) and DNA (592-gene panel or whole exome) for rRCC (N = 20), pRCC (N = 20), and ccRCC samples (N = 392) was performed. Patients with rRCC were significantly younger and more frequently female (median 44.5 years, 75.0% female) as compared with patients with pRCC (68.5 years, 25.0% female; P < .05) and ccRCC (62.0 years, 27.8% female; P < .05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in 2 patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; P < .05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; P < .05). The genomic landscapes of rRCC were sparse with no mutations occurring with a prevalence higher than 10% other than pTERT (18.2% rRCC, 0% pRCC, 9.2% ccRCC). rRCC were associated with significantly less M1 macrophages (0.8%) as compared with pRCC (1.4%) and ccRCC (2.7%) (P < .05), suggesting a cold tumor-immune microenvironment. However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; P < .05). Gene set enrichment analysis showed that rRCC are enriched in genes related to oxidative phosphorylation when compared with both ccRCC and pRCC. Despite having a colder tumor-immune microenvironment than pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor therapy.

Original languageEnglish
Article number100404
Pages (from-to)100404
JournalModern Pathology
Volume37
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • TFE3
  • fusion
  • molecular
  • next-generation sequencing
  • renal cell carcinoma
  • translocation
  • Humans
  • Tumor Microenvironment
  • Male
  • Carcinoma, Renal Cell/genetics
  • Kidney Neoplasms/genetics
  • Female
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics

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