Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma

Abstract

TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC. Understanding the unique traits of a rare kidney cancer type, TFE3-rearranged renal cell carcinoma, is important due to its poor response to usual treatments. This study explores the genetic and metabolic makeup of tRCC, comparing it with clear cell RCC and normal kidney cells. Using a mix of cell culture, whole exome sequencing, and various molecular analyses, the team conducted an experiment to reveal the unique genetic and metabolic profiles of tRCC. The researchers conclude that targeting the metabolic changes in tRCC, specifically through inhibiting PPARGC1A-mediated mitochondrial respiration, offers a new treatment approach. This approach marks a significant step in understanding and potentially treating tRCC. The implications of this study could lead to more effective treatments for patients with this challenging cancer type, emphasizing the importance of metabolic pathways in cancer therapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.