Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma

Abstract

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer that has no standard treatment for advanced disease. We described comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion, certain fusion isoforms and high somatic copy number alteration burdens were associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibited low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis revealed five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which showed association with fusion patterns and prognosis. Specifically, the high angiogenesis/stroma/proliferation cluster exclusively consisted of tumors with ASPSCR1-TFE3 fusion, which was likely to benefit from combination of immune checkpoint and anti-angiogenesis inhibitors. Our findings reveal the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.

Phenotypical screening on metastatic PRCC-TFE3 fusion translocation renal cell carcinoma organoids reveals potential therapeutic agents

“…Furthermore, TFE3 could promote the endolysosomal deprivation reaction by inducing the expression of autolysosomal genes [33,34]. Recently, Zeng et al demonstrated that lysosomal and autophagy pathways were significantly upregulated in TFE3-tRCC [35]. Previous studies indicated that elevated doses of crizotinib can induce autophagy in alveolar rhabdomyosarcoma cells [36] and that autophagy is required for crizotinib-induced apoptosis in MET-amplified gastric cancer cells [23].…”

Chameleon TFE3-translocation RCC and How Gene Partners Can Change Morphology: Accurate Diagnosis Using Contemporary Modalities

“…In addition, compared with CCRCC, TFE3-tRCC also showed significantly higher levels of phospho-S6 and phospho-4EBP1 confirming upregulation of PI3K/AKT/mTOR pathway 34. Because of the complex transcriptomic and genomic landscapes, high molecular heterogeneity and low immunogenicity, TFE3-tRCC remains a therapeutic challenge and requires a combination therapeutic regimens including radiotherapy, chemotherapy, immunotherapy plus MET , TKI , and mTOR inhibitors 25,26,34…”

“…TFE3 gene maps to Xp11.23 is a Transcription Factor binding to IGHM Enhancer 3 and a member of the microphthalmia-associated transcription factor family MiTF 24. This helix-loop-helix leucine zipper transcription factor binds DNA as heterodimer forming an oncogenic fusion in RCC with over 20 different partner genes 25,26. This rearranged TFE3 oncogenic fusion plays a central role in transcriptional dysregulation forming a constitutively active promoter and thus upregulating the expression of >300 genes involved in cell growth, proliferation, and invasiveness including MET , HIF1A , cathepsin-K , CYP17A1 , UPP1 , etc 25–29.…”

“…In contrast, up to 44% of TFE3-tRCC have widespread somatic copy number alterations (CNA) often associated with tumor aggressiveness 31. Gain of 17q and loss 1p, 2p, 6q, 8p, 9p, and 22q, were all associated with poor overall survival; loss of 9p and 22q were additionally associated with higher stage and frequent LN metastases 26,31,32 . ASPSCR1-TFE3 fusion tRCCs were characterized by the most aggressive behavior and frequently harbored loss of 22q, which encodes genes implicated in tumor progression including NF2 , CHEK2 , and SMARCB1 26,33.…”

“…The list of TFE3 fusion partners is growing rapidly, especially since the widespread utilization of RNA-sequencing, and based on our comprehensive literature review of tissue-based studies encountered 22 genes 5–7,12,13,22,26,30,35–44. Two thirds of TFE3-tRCC cases with a known fusion partner and 50% of novel fusion subtypes were published within the last 5 years, and the total number of reported adult tumors with available clinicopathologic features reached 397 cases (cut-off December 1, 2021).…”