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Kidney: Renal cell carcinoma with t(6;11)(p21;q12) MALAT1/TFEB

Written2005-04Pedram Argani, Marc Ladanyi
The Johns Hopkins Hospital/ Surgical Pathology Weinberg Building, Room 2242, 4O1 N. Broadway, Baltimore, MD 21231-2410, USA
Updated2016-08Pedram 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.

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Abstract Review on Renal cell carcinoma with t(6;11)(p21;q12) MALAT1/TFEB, with data on clinics, and the genes involved.


ICD-Topo C649 Kidney
ICD-Morpho 8260/3 Papillary adenocarcinoma, NOS
Atlas_Id 5011
Phylum Urinary system:Kidney:Adult:Renal cell carcinoma:t(6;11)(p21;q13)
Other namesAlpha-TFEB renal cell carcinoma
Note A distinctive renal neoplasm with epithelioid morphology, basement membrane production focal HMB45 immunoreactivity.


    The t(6;11) renal cell carcinomas (RCCs) harbor a specific Alpha (MALAT1)-TFEB gene fusion. Xp11 translocation RCCs harbor gene fusions involving TFE3 transcription factor. 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 Not clear, but a subset of confirmed cases have occurred in children who were exposed to prior cytotoxic chemotherapy, raising the possibility that this tumor may be induced by chemotherapy.
Epidemiology There are approximately 50 reported cases, the Male: Female ratio is 1.4:1. The median age is 31 years (range: 3-68 years).
Pathology On microscopic examination, these neoplasms feature nests and tubules of polygonal epithelioid cells, separated by thin capillaries. Papillary architecture may be seen. The majority of the tumor cells have abundant clear to granular eosinophilic cytoplasm, well-defined cell borders and round nuclei with small nucleoli. However, a second population of smaller epithelioid cells is also characteristic, typically (but not always) clustered around nodules of hyaline basement membrane material within larger acini. Mitoses are rare and necrosis is usually absent. The cases examined have generally been negative for cytokeratins by immunohistochemistry, but all have labeled at least focally for HMB45 and Melan A. The t(6;11) renal carcinomas demonstrate specific nuclear labeling for TFEB protein by IHC while other neoplasms and normal tissues do not. Hence, nuclear labeling for TFEB is a sensitive and specific diagnostic marker for this renal neoplasm with a TFEB gene fusion. TFEB break-apart FISH is generally more reliable in variably-fixed archival material.
Treatment Nephrectomy
Prognosis Unclear at the current time. One case has metastasized and killed the patient, proving that these are malignant neoplasms.

Genes involved and Proteins

Gene Name TFEB
Location 6p21
Dna / Rna TFEB has 10 exons, with the ATG protein initiation codon located within exon 3.
Protein TFEB is a transcription factor with a basic helix-loop-helix DNA binding domain, a leucine zipper dimerization domain18, and a nuclear localization signal, thought to be located C-terminal to the helix-loop-helix domain. TFEB is ubiquitously expressed.
TFEB, TFE3, TFEC and Mitf comprise the members of the microphthalmia transcription factor subfamily, which have homologous DNA binding domains and can 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 MALAT1
Location 11q12
Protein MALAT1 (Alpha) is an intronless, untranslated gene of unknown function.

Result of the chromosomal anomaly

Hybrid Gene
Description The breakpoint on TFEB is within its second intron, just upstream of the TFEB initiation ATG codon, which results in retention of the entire TFEB coding region in the fusion gene. Although the MALAT1 promoter drives expression of the fusion gene, the MALAT1 gene does not contribute to the open reading frame. Therefore, the consequence of the MALAT1-TFEB fusion is dysregulated expression of the normal full-length TFEB protein. The TFEB-MALAT1 fusion gene is also expressed.
Detection RT-PCR is the standard molecular approach for detection of most translocation-associated gene fusions. This is because, in most leukemia and sarcoma translocations, genomic breakpoints are variably positioned within large introns, but the splicing of the transcripts encoded by fusion genes typically results in very consistent fusion points that can be tightly bracketed by appropriate primers to generate relatively small RT-PCR products (e.g. 100-300 bp).
In the t(6;11)(p21;q12), the lack of splicing between MALAT1 and TFEB results in a different and unique fusion transcript in each case that can vary considerably in size (over 1 kb) from case to case. Based on the sizes of these two breakpoint cluster regions, RT-PCR product sizes using a primer at the 5' end of MALAT1 in combination with a reverse primer in exon 3 of TFEB could range in size to over 1.5 kb. This is a technical drawback for molecular diagnosis that could be addressed by using several assays with different MALAT1 primers scattered from the 5' to the 3' end of the gene. However the unique features of the MALAT1 gene as a translocation partner should result in a lack of splicing across the intron rearranged by the translocation. Indeed, this seems to be the case, since in all three cases with data on both the genomic junction sequence and the fusion transcript, the sequences have been identical. This indicates that the DNA PCR and RT-PCR products will be identical if a reverse primer that binds to TFE3 exon 3 is used. Because it is easier to isolate and amplify 1 to 1.5 kb target DNAs from clinical tumor samples than target RNAs of the same size (given the greater lability of RNA), detecting this fusion by long range DNA PCR may be a useful alternative for molecular diagnosis.
Fusion Protein
Note The MALAT1-TFEB gene fusion results in dysregulated expression of native TFEB protein.
Description TFEB protein that is overexpressed as a result of the MALAT1-TFEB gene fusion localizes to the nucleus as determined by immunohistochemistry. While it is ubiquitously expressed, native TFEB in cells without this translocation is not detectable by this assay.


A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation.
Argani P, Hawkins A, Griffin CA, Goldstein JD, Haas M, Beckwith JB, Mankinen CB, Perlman EJ
The American journal of pathology. 2001 ; 158 (6) : 2089-2096.
PMID 11395386
Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR.
Argani P, Laé M, Hutchinson B, Reuter VE, Collins MH, Perentesis J, Tomaszewski JE, Brooks JS, Acs G, Bridge JA, Vargas SO, Davis IJ, Fisher DE, Ladanyi M
The American journal of surgical pathology. 2005 ; 29 (2) : 230-240.
PMID 15644781
Molecular Confirmation of the t(6;11)(p21;q12) Renal Cell Carcinoma in Archival Paraffin-Embedded Material using a Break-Apart TFEB FISH assay Expands its Clinicopathologic Spectrum..
Argani P, Yonescu R, Morsberger L,Morris K, Netto GJ, Smith N, Gonzalez N, Illei PB, Ladanyi M, Griffin CA.
Am J Surg Pathol 2012;36: 1516-1526.
PMID 22892601
Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation.
Davis IJ, Hsi BL, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez-Atayde AR, Argani P, Ladanyi M, Fletcher JA, Fisher DE
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (10) : 6051-6056.
PMID 12719541
Two cases of renal cell carcinoma, clear cell type, revealing a t(6;11)(p21;q13).
Dijkhuizen T, van den Berg E, Storkel S, van Kessel AG, Janssen B, de Jong B
Cancer Genet Cytogenet. 1996 ; 91 : page 141.
Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution.
Kuiper RP, Schepens M, Thijssen J, van Asseldonk M, van den Berg E, Bridge J, Schuuring E, Schoenmakers EF, van Kessel AG
Human molecular genetics. 2003 ; 12 (14) : 1661-1669.
PMID 12837690
t6;11 renal cell tumor. A clinicopathologic study of 2 cases in adults.
Martignoni G, Tardanico R, Pea M, Pecciarini L, Gobbo S, Brunelli M, Balzarini P, Macri E, Doglioni C
Mod Pathol. 2005 ; 18.
t(6;11) renal cell carcinoma (RCC): Expanded immunohistochemical profile exphasizing novel RCC markers and report of ten new genetically-confirmed cases.
Smith N, Illei P, Allaf M, Gonzalez N, Morris K, Hicks J, De Marzo A, Reuter VE, Amin MB, Epstein JI, Netto G, Argani P.
Am J Surg Pathol 2014;38: 604-614.
PMID 24618616
Distinctive chromosomal translocations in pediatric renal cell carcinoma.
Yeh Y, Vargas S, Fletcher JA, Perez Atayde AR
Mod Pathol. 2002 ; 15 : page 7.


This paper should be referenced as such :
Argani P, Ladanyi M
Kidney: Renal cell carcinoma with t(6;11)(p21;q12) MALAT1/TFE
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :
History of this paper:
Argani, P ; Ladanyi, M. Kidney: t(6;11)(p21;q12) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2005;9(3):259-261.

Translocations implicated (Data extracted from papers in the Atlas)

 t(6;11)(p21;q12) MALAT1/TFEB

External links

Mitelman database t(6;11)(p21;q12) MALAT1/TFEB [Case List]    t(6;11)(p21;q12) MALAT1/TFEB [Association List] Mitelman database (CGAP - NCBI)
arrayMap Topo ( C64) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Disease databaseKidney: Renal cell carcinoma with t(6;11)(p21;q12) MALAT1/TFEB
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

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