Kidney: Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3

2005-08-01   Pedram Argani , Marc Ladanyi 

1.Department of Pathology, The Johns Hopkins Hospital, Baltimore MD (PA) pargani@jhmi.edu; Dept. of Pathology, , MSKCC, 1275 York Avenue, New York, NY 10021 (ML) USA.

Abstract

Review on Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3, with data on clinics, and the genes involved.

Classification

Classification

This renal cell carcinoma belongs to the family of Xp11 translocation renal carcinomas. Xp11 translocation renal cell carcinomas (RCCs) harbor gene fusions involving TFE3 transcription factor. The t(6;11) RCCs harbor a specific MALAT1 (Alpha) - TFEB gene fusion. TFEB and TFE3 belong to the same MiT subfamily of transcription factors. Because of similarities at the clinical, morphologic, immunohistochemical, and genetic levels, the Xp11 translocation RCCs and t(6;11) RCCs are currently grouped together under the category of MiT family translocation renal cell carcinoma.

Clinics and Pathology

Etiology

Unclear

Epidemiology

Fewer than 10 cases reported in the literature, median age is 36 years.

Pathology

NONO-TFE3 RCCs frequently have papillary architecture and clear cells with subnuclear vacuoles. Rare Xp11 translocation perivascular epithelioid cell tumors (PEComas) harbor the same gene fusion.

Treatment

Surgical excision.

Evolution

Unknown.

Cytogenetics

Cytogenetics morphological

inv(X)(p11.2q12).

Genes Involved and Proteins

Gene name

TFE3 (transcription factor E3)

Location

Xp11.23

Dna rna description

The TFE3 gene includes a 5 untranslated region, 8 exons, and a 3 untranslated region.

Protein description

TFE3 is a transcription factor with a basic helix-loop-helix DNA binding domain and a leucine zipper dimerization domain. TFE3 contains a nuclear localization signal, encoded at the junction of exons 5 and 6, which is retained within all known TFE3 fusion proteins. TFE3 protein is 575 amino acids, and is ubiquitously expressed. TFE3, TFEB, TFEC and MITF comprise the members of the microphthalmia transcription factor subfamily, which have homologous DNA binding domains and in fact bind to a common DNA sequence. These four transcription factors may homo- or heterodimerize to bind DNA, and they may have functional overlap.

Gene name

NONO (non-POU domain containing, octamer-binding)

Location

Xq13.1

Protein description

NONO is a 471 amino acid protein with several distinctive domains. From N-terminus to C-terminus, it has :
  • 1) an N-terminal basic region composed entirely of Proline, Glutamine, and Histidine,
  • 4) a short C-terminal Proline-rich region.

  • 3) a helix-turn helix domain followed by a series of charged amino acids that likely forms a DNA-binding unit,SFPQ and NONO are highly homologous and related proteins. NONO has a region of 320 amino acids with a 71% identity and a 7% similarity to a 320 amino acid region within PSF. Both proteins have both DNA and RNA binding domains, which underlies their multifunctionality. Indeed, these proteins have been implicated in both transcriptional activation and splicing. Both proteins are known to bind to the DNA binding domains of nuclear hormone receptors (such as the thyroid hormone receptors and the retinoid X receptors), and modulate transcriptional activation. These proteins bind to each other, select the same optimal RNA sequence from RNA pools, and have been associated with spliceosomes. Both have been shown to bind to the C-terminal domain of RNA polymerase II, where they may couple pre-mRNA splicing and RNA processing. SFPQ and NONO enhance Topoisomerase I cleavage of DNA, and induce its jumping to other DNA helices after cleavage. Finally, both have been shown to bind and retain defective and hyperedited mRNAs within the nucleus, preventing translation of mutated proteins.
  • Result of the chromosomal anomaly

    Description

    5 NONO - 3 TFE3

    Description

    The inv (X)(p11.2q12) results in fusion of virtually the entire sequence of NONO/p54nrb with the C-terminal portion of the TFE transcription factor that contains the basic helix-loop-helix (bHLH) DNA binding domain and Leucine Zipper domain.

    Highly cited references

    Pubmed IDYearTitleCitations
    250488602014Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.101
    172831222007TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition.83
    129176402003A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23).73
    269750362016TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers.50
    297130412018RNA sequencing of Xp11 translocation-associated cancers reveals novel gene fusions and distinctive clinicopathologic correlations.18
    113139422001PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors.15
    337410272021Low expression of TRAF3IP2-AS1 promotes progression of NONO-TFE3 translocation renal cell carcinoma by stimulating N6-methyladenosine of PARP1 mRNA and downregulating PTEN.12
    279348792017Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement.12
    268446762016Xp11 neoplasm with melanocytic differentiation of the prostate harbouring the novel NONO-TFE3 gene fusion: report of a unique case expanding the gene fusion spectrum.7
    232246032012A renal epithelioid angiomyolipoma/perivascular epithelioid cell tumor with TFE3 gene break visualized by FISH.6
    335922662021The positive regulation loop between NRF1 and NONO-TFE3 fusion promotes phase separation and aggregation of NONO-TFE3 in NONO-TFE3 tRCC.5
    291509592018NONO ubiquitination is mediated by FBW7 and GSK3 β via a degron lost upon chromosomal rearrangement in cancer.4
    280096052017Melanotic PEComa of the Sinonasal Mucosa With NONO-TFE3 Fusion: An Elusive Mimic of Sinonasal Melanoma.4
    195634132009Adult-onset renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusion with smooth muscle stroma and abnormal vessels.3
    350425252022CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3.2
    341480642021Diagnostic utility of one-stop fusion gene panel to detect TFE3/TFEB gene rearrangement and amplification in renal cell carcinomas.2
    338457432021NONO-TFE3 Fusion Promotes Aerobic Glycolysis and Angiogenesis by Targeting HIF1A in NONO-TFE3 Translocation Renal Cell Carcinoma.1
    301076602018[Clinicopatholigic features of renal cell carcinoma associated with chromosome X inversion harboring gene fusions involving TFE3].1
    312779532019Xp11.2 translocation renal neoplasm with features of TFE3 rearrangement associated renal cell carcinoma and Xp11 translocation renal mesenchymal tumor with melanocytic differentiation harboring NONO-TFE3 fusion gene.1
    3589708520225mC and H3K9me3 of TRAF3IP2 promoter region accelerates the progression of translocation renal cell carcinoma.0
    354472812022Up-regulation of NMRK2 mediated by TFE3 fusions is the key for energy metabolism adaption of Xp11.2 translocation renal cell carcinoma.0
    345214392021Correction to: Low expression of TRAF3IP2-AS1 promotes progression of NONO-TFE3 translocation renal cell carcinoma by stimulating N6-methyladenosine of PARP1 mRNA and downregulating PTEN.0
    326769672021Ocular PEComas are frequently melanotic and TFE3-translocated: report of two cases including the first description of PRCC-TFE3 fusion in PEComa.0
    330049952020The suitability of NONO-TFE3 dual-fusion FISH assay as a diagnostic tool for NONO-TFE3 renal cell carcinoma.0
    318180682019[Xp11 neoplasma with melanocytic differentiation: a clinicopathological analysis].0
    297838122018[Renal cell carcinoma associated with Xp11.2 translocation/NONO-TFE3 gene fusion: report of a case].0
    214249372011Re-evaluation of histological type by immunohistochemical and genetic study of transcription factors (TFE3 and TFEB) of VHL gene mutation-negative clear cell renal cell carcinoma and other special types of renal tumor.0

    Bibliography

    Pubmed IDLast YearTitleAuthors
    90012211997The intracisternal A-particle proximal enhancer-binding protein activates transcription and is identical to the RNA- and DNA-binding protein p54nrb/NonO.Basu A et al
    93939821997Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma.Clark J et al
    83719831993Purification and cDNA cloning of HeLa cell p54nrb, a nuclear protein with two RNA recognition motifs and extensive homology to human splicing factor PSF and Drosophila NONA/BJ6.Dong B et al
    123584292002Splicing and transcription-associated proteins PSF and p54nrb/nonO bind to the RNA polymerase II CTD.Emili A et al
    128100692003p54nrb acts as a transcriptional coactivator for activation function 1 of the human androgen receptor.Ishitani K et al
    124034702002PSF and p54nrb bind a conserved stem in U5 snRNA.Peng R et al
    124172962002PSF and p54(nrb)/NonO--multi-functional nuclear proteins.Shav-Tal Y et al

    Citation

    Pedram Argani ; Marc Ladanyi

    Kidney: Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3

    Atlas Genet Cytogenet Oncol Haematol. 2005-08-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5057/kidney-renal-cell-carcinoma-with-inv(x)(p11q12)-nono-tfe3

    Historical Card

    0000-00-00 Kidney: Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3 by  Pedram Argani,Marc Ladanyi 

    Department of Pathology, The Johns Hopkins Hospital, Baltimore MD (PA) pargani@jhmi.edu; Dept. of Pathology, , MSKCC, 1275 York Avenue, New York, NY 10021 (ML) USA.