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Midline Carcinoma: t(15;19)(q14;p13) BRD4/NUTM1

Written2007-02Anna Collin
Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden

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Identity

Atlas_Id 5474
Phylum Lung, Heart, Skin, Other::Other
Other namesMediastinal carcinoma with chromosome translocation t(15;19)
Midline carcinoma of children and young adults with NUT rearrangement
Midline carcinoma with t(15;19)
Poorly differentiated carcinoma with t(15;19)
Poorly differentiated thymic carcinoma
t(15;19) positive tumor

Clinics and Pathology

Disease Carcinoma with t(15;19) translocation
Phenotype / cell stem origin It has been suggested that tumor cells derive from early epithelial progenitor cells.
Embryonic origin The majority of the cases presumably derive from various (midline) epithelial surfaces. One tumor, localized to the iliac bone and staining negative for epithelial, endothelial, germ cell and neuroendocrine markers has been reported, suggesting that the tumor might also derive from non-epithelial structures.
Etiology Unknown
Epidemiology A total of 13 cases have been reported to date. All tumors occurred in children or young adults with a median age of 15 years of age (range 3-35). There seem to be no sex predilection (8 males, 5 females).
Clinics The growth pattern is typically aggressive and locally invasive. Metastatic growth is common in particular in bone, but also in lymph nodes and lungs.
Cytology Focal reactivity with pan-cytokeratin markers. Negative for CD30, CD45, PLAP, HMB45, S100 and neuroendocrine markers.
Pathology The tumor cells are typically undifferentiated, of intermediate size and the mitotic index is high.
Treatment Intensive combined chemotherapy and occasionally radiotherapy.
Prognosis Extremely poor. Among the cases reported so far, the median survival time was 18 weeks (range 6-67).
It has been suggested that a critical prognostic difference exists between BRD4-NUT/t(15;19) positive tumors and tumors where NUT is rearranged but fused to an as yet unknown partner.

Cytogenetics

Cytogenetics
Morphological
The characteristic t(15;19) has been observed in all reported cases. The reported breakpoints on chromosome 15 have varied (15q11-q15). The breakpoints on chromosome 19 clustered to 19p13 in the majority of the cases. In one case the breakpoint was interpreted as 19q13.
Cytogenetics Molecular Various FISH protocols for the detection of 15q and 19p rearrangements, strongly indicating the presence of a t(15;19), have been reported. The material used has been paraffin-embedded sections of tumor biopsy or metaphase spreads of cultured tumor tissue. The t(15;19) is typically seen as the sole change. In one case a variant t(11;15;19) was reported.
Probes Probes for NUT: RP11-194H7 covering the gene or BAC 87M17 and YAC 766E7 flanking the gene.
Probes for BRD4: RP11-637P24 covering the gene or BACs 1H8+64O3 and BACs 412E10+3D4 flanking the gene.
Variants t(15;?)(q14;?) leading to rearrangement and fusion of NUT to an unknown partner gene.

Genes involved and Proteins

Gene Name NUTM1
Location 15q14 (position 32425358-32437221 on the chromosome 15 genomic sequence according to the UCSC database; assembly of May 2004)
Dna / Rna The gene consists of 7 exons that span approximately 12 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and the stop codon are predicted to exon 1 and exon 7, respectively. The corresponding wildtype mRNA transcript is 3.6 kb.
Protein The open reading frame is predicted to encode a 1127 amino acid protein with an estimated molecular weight of 120 kDa. The protein is nuclear and Northern blot analysis has indicated that the normal expression of the NUT gene is highly restricted to the testis.

Gene Name BRD4
Location 19p13 (position 15252262-15209302 on the chromosome 19 genomic sequence according to the UCSC database; assembly of May 2004).
Dna / Rna The gene consists of 20 exons that span approximately 43 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and stop codon are located to exon 2 and exon 20, respectively. Two isoforms of BRD4 have been reported. The BRD4 long isoform encodes a 6.0 kb mRNA that corresponds to the full length transcript. The BRD4 short isoform encodes a 4.4 kb mRNA that corresponds to an alternative splicing variant lacking exons 12-20.
Protein The open reading frame encodes a 1362 amino acid protein with a molecular weight of 200 kDa. The protein is nuclear and Northern blot analysis has shown an ubiquitous normal expression of both BRD4 isoforms.

Result of the chromosomal anomaly

Hybrid Gene
Description The t(15;19)(q14;p13) results in a BRD4-NUT chimeric gene where exon 10 of BRD4 is fused to exon 2 of NUT.
Detection The hybrid gene can be visualized by FISH using gene specific probes or by RT-PCR.
Fusion Protein
Description The BRD4-NUT fusion protein is composed of the N-terminal of BRD4 (amino acids 1-720 out of 1372) and almost the entire protein sequence of NUT (amino acids 6-1127). The N-terminal of BRD4 includes bromodomains 1 and 2 and other, less well characterized functional domains.
Oncogenesis It has been suggested that the oncogenic effect of the NUT-BRD4 fusion is caused not only by the abnormal regulation of NUT by BRD4 promotor elements but also by the consequent ectopic expression of NUT in non-germinal tissues.
  

Bibliography

Chromosome 19 translocation, overexpression of Notch3, and human lung cancer.
Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR, Carbone DP
Journal of the National Cancer Institute. 2000 ; 92 (16) : 1355-1357.
PMID 10944559
 
Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy.
Engleson J, Soller M, Panagopoulos I, Dahlén A, Dictor M, Jerkeman M
BMC cancer. 2006 ; 6 : page 69.
PMID 16542442
 
Midline carcinoma of children and young adults with NUT rearrangement.
French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, Nose V, Vargas SO, Moschovi M, Tzortzatou-Stathopoulou F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004 ; 22 (20) : 4135-4139.
PMID 15483023
 
BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.
French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA
Cancer research. 2003 ; 63 (2) : 304-307.
PMID 12543779
 
Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19).
Kees UR, Mulcahy MT, Willoughby ML
The American journal of pediatric hematology/oncology. 1991 ; 13 (4) : 459-464.
PMID 1785673
 
Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma.
Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T, Miyoshi I
Cancer research. 1991 ; 51 (12) : 3327-3328.
PMID 2040007
 
Disseminated mediastinal carcinoma with chromosomal translocation (15;19). A distinctive clinicopathologic syndrome.
Lee AC, Kwong YI, Fu KH, Chan GC, Ma L, Lau YL
Cancer. 1993 ; 72 (7) : 2273-2276.
PMID 8374886
 
Carcinoma with t(15;19) translocation.
Marx A, French CA, Fletcher JA
In..
 
Successful treatment of a child with t(15;19)-positive tumor.
Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA
Pediatric blood & cancer. 2007 ; 49 (7) : 1015-1017.
PMID 16435379
 
Translocation (11;15;19): a highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients.
Toretsky JA, Jenson J, Sun CC, Eskenazi AE, Campbell A, Hunger SP, Caires A, Frantz C, Hill JL, Stamberg J
American journal of clinical oncology. 2003 ; 26 (3) : 300-306.
PMID 12796605
 
Upper respiratory tract carcinoma with chromosomal translocation 15;19: evidence for a distinct disease entity of young patients with a rapidly fatal course.
Vargas SO, French CA, Faul PN, Fletcher JA, Davis IJ, Dal Cin P, Perez-Atayde AR
Cancer. 2001 ; 92 (5) : 1195-1203.
PMID 11571733
 
Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.
You J, Croyle JL, Nishimura A, Ozato K, Howley PM
Cell. 2004 ; 117 (3) : 349-360.
PMID 15109495
 

Citation

This paper should be referenced as such :
Collin, A
Carcinoma with t(15;19) translocation
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):249-251.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/Carcinot1519q14p13ID5474.html


Other genes implicated (Data extracted from papers in the Atlas) [ 4 ]

Genes BRD3 BRD4 EGLN1 NUTM1

Translocations implicated (Data extracted from papers in the Atlas)

 t(15;19)(q14;p13) BRD4/NUTM1

External links

Mitelman database t(15;19)(q14;p13) BRD4/NUTM1 [Case List]    t(15;19)(q14;p13) BRD4/NUTM1 [Association List] Mitelman database (CGAP - NCBI)
arrayMap arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseBRD4/NUTM1[MCList]    BRD4 (19p13.12) NUTM1 (15q14)   
Mitelman databaseBRD4/NUTM1[MCList]    BRD4 (19p13.12) NUTM1 (15q14)   der(15)(q14)
 
Disease databaseMidline Carcinoma: t(15;19)(q14;p13) BRD4/NUTM1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


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