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

Eric C Kauffman1, Christopher J Ricketts1, Soroush Rais-Bahrami1

  • 1Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, CRC Room 1-5940, Bethesda, MD 20892, USA.

Nature Reviews. Urology
|July 23, 2014
PubMed

Insights

Gene fusions involving TFE3 or TFEB drive renal cell carcinoma (RCC) tumorigenesis through unclear mechanisms. Identifying key oncogenic pathways is crucial for developing targeted therapies for this kidney cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Gene fusions involving TFE3 or TFEB have been known in sporadic renal cell carcinoma (RCC) for nearly two decades.
  • Recent data confirms the significance of these gene fusions, with SFPQ-TFE3 fusions found in 1.2% of clear cell RCC tumors.
  • The precise molecular mechanisms driving renal-specific tumorigenesis by TFE3/TFEB remain largely unelucidated.

Purpose of the Study:

  • To review and synthesize current knowledge on TFE3/TFEB gene fusions in renal cell carcinoma.
  • To highlight the known molecular pathways regulated by TFE3 and TFEB implicated in carcinogenesis.
  • To emphasize the need for determining critical pathways for identifying novel therapeutic targets in RCC.

Main Methods:

  • Review of published literature and genomic data, including findings from The Cancer Genome Atlas Network.
  • Characterization of identified TFE3 and TFEB gene fusions at the mRNA transcript level.
  • Analysis of molecular pathways known to be regulated by TFE3 or TFEB proteins in the context of cancer.

Main Results:

  • Five distinct TFE3 gene fusions (PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3, NONO-TFE3, CLTC-TFE3) and one TFEB fusion (MALAT1-TFEB) have been identified in RCC.
  • TFE3/TFEB proteins regulate multiple pathways involved in carcinogenesis, including TGFβ, ETS, E-cadherin, CD40L, mTORC1, metabolism, folliculin, and cell cycle arrest.
  • SFPQ-TFE3 fusions were identified in 1.2% of clear cell RCC tumors surveyed by The Cancer Genome Atlas Network.

Conclusions:

  • TFE3/TFEB gene fusions are recurrent oncogenic drivers in a subset of renal cell carcinomas.
  • Understanding the specific roles of TFE3/TFEB in regulating key oncogenic pathways is critical for advancing RCC research.
  • Identifying the most impactful pathways will guide the development of effective, targeted therapeutic strategies for RCC patients.

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