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

2007-02-01   Anna Collin 

1.Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden

Clinics and Pathology

Phenotype stem cell 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.

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.

Additional anomalies

The t(15;19) is typically seen as the sole change. In one case a variant t(11;15;19) was reported.

Variants

t(15;?)(q14;?) leading to rearrangement and fusion of NUT to an unknown partner gene.

Genes Involved and Proteins

Gene name

NUTM1 (nuclear protein in testis)

Location

15q14

Dna rna description

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 description

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

19p13.12

Dna rna description

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 description

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

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 protocole

The hybrid gene can be visualized by FISH using gene specific probes or by RT-PCR.

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

Pubmed IDLast YearTitleAuthors
109445592000Chromosome 19 translocation, overexpression of Notch3, and human lung cancer.Dang TP et al
165424422006Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy.Engleson J et al
154830232004Midline carcinoma of children and young adults with NUT rearrangement.French CA et al
125437792003BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.French CA et al
17856731991Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19).Kees UR et al
20400071991Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma.Kubonishi I et al
83748861993Disseminated mediastinal carcinoma with chromosomal translocation (15;19). A distinctive clinicopathologic syndrome.Lee AC et al
164353792007Successful treatment of a child with t(15;19)-positive tumor.Mertens F et al
127966052003Translocation (11;15;19): a highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients.Toretsky JA et al
115717332001Upper respiratory tract carcinoma with chromosomal translocation 15;19: evidence for a distinct disease entity of young patients with a rapidly fatal course.Vargas SO et al
151094952004Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.You J et al

Citation

Anna Collin

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

Atlas Genet Cytogenet Oncol Haematol. 2007-02-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5474/midline-carcinoma-t(15;19)(q14;p13)-brd4-nutm1