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

Written2016-08Pedram Argani, Marc Ladanyi
Department of Pathology, The Johns Hopkins Hospital, Baltimore MD (PA); Dept. of Pathology, , MSKCC, 1275 York Avenue, New York, NY 10021 (ML) USA.
This article is an update of :
2005-08Pedram Argani, Marc Ladanyi
Dept. of Pathology, room S-801, MSKCC, 1275 York Avenue, New York, NY 10021, USA

(Note : for Links provided by Atlas : click)


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


ICD-Topo C649 Kidney
ICD-Morpho 8260/3 Papillary adenocarcinoma, NOS
Atlas_Id 5057
Phylum Urinary system: Kidney::Renal cell carcinoma
WHO/OMS Classification Urinary system
Other namesNONO-TFE3 renal cell carcinoma


    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.



Genes involved and Proteins

Gene NameTFE3 (transcription factor E3)
Location Xp11.23
Dna / Rna The TFE3 gene includes a 5' untranslated region, 8 exons, and a 3' untranslated region.
Protein 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 NameNONO (non-POU domain containing, octamer-binding)
Location Xq13.1
Protein 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,
  • 2) a pair of RNA recognition motifs,
  • 3) a helix-turn helix domain followed by a series of charged amino acids that likely forms a DNA-binding unit,
  • 4) a short C-terminal Proline-rich region.

    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

    Hybrid Gene
    Description 5' NONO - 3' TFE3
    Fusion Protein
    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.


    The intracisternal A-particle proximal enhancer-binding protein activates transcription and is identical to the RNA- and DNA-binding protein p54nrb/NonO
    Basu A, Dong B, Krainer AR, Howe CC
    Mol Cell Biol 1997 Feb;17(2):677-86
    PMID 9001221
    Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma
    Clark J, Lu YJ, Sidhar SK, Parker C, Gill S, Smedley D, Hamoudi R, Linehan WM, Shipley J, Cooper CS
    Oncogene 1997 Oct;15(18):2233-9
    PMID 9393982
    Purification 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, Horowitz DS, Kobayashi R, Krainer AR
    Nucleic Acids Res 1993 Aug 25;21(17):4085-92
    PMID 8371983
    Splicing and transcription-associated proteins PSF and p54nrb/nonO bind to the RNA polymerase II CTD
    Emili A, Shales M, McCracken S, Xie W, Tucker PW, Kobayashi R, Blencowe BJ, Ingles CJ
    RNA 2002 Sep;8(9):1102-11
    PMID 12358429
    p54nrb acts as a transcriptional coactivator for activation function 1 of the human androgen receptor
    Ishitani K, Yoshida T, Kitagawa H, Ohta H, Nozawa S, Kato S
    Biochem Biophys Res Commun 2003 Jul 4;306(3):660-5
    PMID 12810069
    PSF and p54nrb bind a conserved stem in U5 snRNA
    Peng R, Dye BT, Pérez I, Barnard DC, Thompson AB, Patton JG
    RNA 2002 Oct;8(10):1334-47
    PMID 12403470
    PSF and p54(nrb)/NonO--multi-functional nuclear proteins
    Shav-Tal Y, Zipori D
    FEBS Lett 2002 Nov 6;531(2):109-14
    PMID 12417296


    This paper should be referenced as such :
    Pedram Argani, Marc Ladanyi
    Kidney: Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3
    Atlas Genet Cytogenet Oncol Haematol. 2017;21(8):308-309.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :
    History of this paper:
    Argani, P ; Ladanyi, M. Kidney: inv(X)(p11.2;q12) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2006;10(1):31-32.

    Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

    Genes TFE3

    Translocations implicated (Data extracted from papers in the Atlas)

     inv(X)(p11q12) NONO/TFE3

    External links

    Mitelman database inv(X)(p11q12) [CaseList]     inv(X)(p11q12) [Transloc - MCList]   NONO/TFE3 Fusion - MCList]
    COSMIC[ NONO ]   [ TFE3 ]
    arrayMap Topo ( C64) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
    Disease databaseKidney: Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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