It has been suggested that tumor cells derive from early epithelial progenitor cells.

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.

Unknown

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).

The growth pattern is typically aggressive and locally invasive. Metastatic growth is common in particular in bone, but also in lymph nodes and lungs.

Focal reactivity with pan-cytokeratin markers. Negative for CD30, CD45, PLAP, HMB45, S100 and neuroendocrine markers.

The tumor cells are typically undifferentiated, of intermediate size and the mitotic index is high.

Intensive combined chemotherapy and occasionally radiotherapy.

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.

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.

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 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.

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

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

NUTM1 (nuclear protein in testis)

15q14

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.

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.

BRD4 (bromodomain containing 4)

19p13.12

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.

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.

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.

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

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.

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.