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Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers

Key Points

  • Recent large-scale next-generation genetic analyses underscore the frequent occurrence and importance of gene fusion events—including those involving the MiT transcription factor family—in renal cell carcinoma (RCC)

  • Six MiT family gene fusions (five involving TFE3 and one involving TFEB) have been identified in patients with RCC, most of which demonstrate heterogeneity in mRNA transcript structure across different tumours

  • Common to all TFE3 and TFEB fusion isoforms is retention of the wild-type protein C-terminus, which includes DNA-binding, dimerization, and nuclear localization domains, but not the transcriptional activation domain

  • The most widely accepted model of TFE-fusion oncogenesis is the introduction of a constitutively active promoter leading to dysregulated TFE transcriptional activity

  • Many proteins (including TGFβ, ETS-1, E-cadherin, folliculin, mTORC1) and cellular processes (autophagy, insulin-dependent metabolism, retinoblastoma-dependent cell cycle arrest) are regulated by wild type TFE proteins; dysregulation could drive tumorigenesis

  • Given the lack of a standard-of-care for the systemic treatment of TFE-fusion RCC, pinpointing the most promising molecular targets for novel therapeutics should be a primary focus of ongoing research

Abstract

Despite nearly two decades passing since the discovery of gene fusions involving TFE3 or TFEB in sporadic renal cell carcinoma (RCC), the molecular mechanisms underlying the renal-specific tumorigenesis of these genes remain largely unclear. The recently published findings of The Cancer Genome Atlas Network reported that five of the 416 surveyed clear cell RCC tumours (1.2%) harboured SFPQ–TFE3 fusions, providing further evidence for the importance of gene fusions. A total of five TFE3 gene fusions (PRCC–TFE3, ASPSCR1–TFE3, SFPQ–TFE3, NONO–TFE3, and CLTC–TFE3) and one TFEB gene fusion (MALAT1–TFEB) have been identified in RCC tumours and characterized at the mRNA transcript level. A multitude of molecular pathways well-described in carcinogenesis are regulated in part by TFE3 or TFEB proteins, including activation of TGFβ and ETS transcription factors, E-cadherin expression, CD40L-dependent lymphocyte activation, mTORC1 signalling, insulin-dependent metabolism regulation, folliculin signalling, and retinoblastoma-dependent cell cycle arrest. Determining which pathways are most important to RCC oncogenesis will be critical in discovering the most promising therapeutic targets for this disease.

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Figure 1: ClustalW alignment of the protein sequences of TFE3, TFEB, TFEC, and MiTF.
Figure 2: TFE3 gene fusions.
Figure 3: MALAT1–TFEB gene fusions.
Figure 4: TFE3 and TFEB functions that could potentially contribute to carcinogenesis.

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E.C.K., C.J.R., S.R.-B. and W.M.L. researched data for the article. All authors made a substantial contribution to discussion of content, writing and reviewing/editing the manuscript before submission.

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Correspondence to W. Marston Linehan.

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Kauffman, E., Ricketts, C., Rais-Bahrami, S. et al. Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers. Nat Rev Urol 11, 465–475 (2014). https://doi.org/10.1038/nrurol.2014.162

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