Carcinoma with t(15;19) translocation

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Carcinoma with t(15;19) translocation

Identity

Other names Mediastinal 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 NUT (nuclear protein in testis)

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 (bromodomain containing 4)

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

Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19).

Kees UR, Mulcahy MT, Willoughby MLN.

Am J Pediatr Hematol Oncol. 1991; 13: 459-464.

PMID 1785673

Novel t(15;19) chromosome abnormality in a thymic carcinoma.

Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T, Miyoshi I.

Cancer Res. 1991; 51: 3327-3328.

PMID 2040007

Disseminated mediastinal carcinoma with chromosomal translocation (15;19). A distinctive clinicopathologic syndrome.

Lee ACW, Kwong Y-I, Fu KH, Chan GCF, Ma L, Lau Y-I.

Cancer. 1993; 72: 2273-2276.

PMID 8374886

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.

J Natl Cancer Inst. 2000; 92: 1355-1357.

PMID 10944559

BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).

French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA.

Am J Pathol. 2001; 159: 1987-1992.

PMID 11733348

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: 1195-1203.

PMID 11571733

BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.

French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA.

Cancer Res. 2003; 63: 304-307.

PMID 12543779

Translocation t(11;15;19): a highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients.

Toretsky JA, Jenson J, Sun C-C, Eskenazi AE, Campbell A, Hunger SP, Caires A, Frantz C, Hill JL, Stamberg J.

Am J Clin Oncol. 2003; 26: 300-306.

PMID 12796605

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-Stathopoulo F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA.

J Clin Oncol. 2004; 22: 4135-4139.

PMID 15483023

Carcinoma with t(15;19) translocation.

Marx A, French CA, Fletcher JA.

In: World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, thymus, pleura and heart. Travis WD, Brambilla E, Muller-Hermelink K, Harris CC, editors. Oxford University Press 2004. pp. 185-186.

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 P.

Cell. 2004; 117: 349-360.

PMID 15109495

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, Dahlen A, Dictor M, Jerkeman M.

BMC Cancer. 2006; 6: 69.

PMID 16542442

Successful treatment of a child with t(15;19)-positive tumor.

Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA.

Pediatr Blood Cancer. 2006.

PMID 16435379

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Contributor(s)

Written 02-2007 Anna Collin

Citation

This paper should be referenced as such :
Collin A . Carcinoma with t(15;19) translocation. Atlas Genet Cytogenet Oncol Haematol. February 2007 .
URL : http://AtlasGeneticsOncology.org/Tumors/Carcinot1519q14p13ID5474.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Apr 17 14:14:27 2008

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Other names	Mediastinal 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

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 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.

Gene Name	NUT (nuclear protein in testis)
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 (bromodomain containing 4)
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.

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.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed