Molecular Characterization of TFE3-rearranged Renal Cell Carcinoma, A Comparative Study with Papillary and Clear Cell Renal Cell Carcinomas.

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. rRCC patients were significantly younger and more frequently female (median 44.5 years (y), 75.0% female) as compared to pRCC (68.5 y, 25.0% female; p < 0.05) and ccRCC (62.0 y, 27.8% female; p < 0.05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in two patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; p<0.05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; p<0.05). 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 to pRCC (1.4%) and ccRCC (2.7%) (p < 0.05), suggesting a cold tumor immune microenvironment (TME). However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; p < 0.05). Gene set enrichment analysis showed rRCC are enriched in genes related to oxidative phosphorylation when compared to both ccRCC and pRCC. Despite having a relatively cold TME compared to pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor (ICI) therapy.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2023 Dec 15 [Epub ahead of print]

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

Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address: ., Caris Life Sciences, Phoenix, AZ, USA., Fox Chase Cancer Center, Philadelphia, PA, USA., University Hospitals Seidman Cancer Center, Cleveland, OH, USA., Brown University, Providence, RI, USA., Karmanos Cancer Institute, Detroit, MI, USA., University of Minnesota, Minneapolis, MN, USA., Stephenson Cancer Center, The University of Oklahoma Health Sciences., Department of Pathology, The Johns Hopkins University School of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland, USA., University of California San Diego, San Diego, CA, USA.

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