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.

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