Abstract
NUT midline carcinoma (NMC) is a fatal cancer that arises in various tissues along the upper midline of the body. The defining molecular feature of NMC is a chromosomal translocation that joins (in the majority of cases) the nuclear testis gene NUT (NUTM1) to the bromodomain protein family member 4 (BRD4) and thereby creating a fusion oncogene that disrupts cellular differentiation and drives the disease. In this study, we report the case of an adolescent NMC patient presenting with severe facial pain, proptosis and visual impairment due to a mass arising from the ethmoid sinus that invaded the right orbit and frontal lobe. Treatment involved radical resection, including exenteration of the affected eye with the view to consolidate treatment with radiation therapy; however, the patient experienced rapid tumor progression and passed away 79 days post resection. Molecular analysis of the tumor tissue identified a novel in-frame BRD4-NUT transcript, with BRD4 exon 15 fused to the last 124 nucleotides of NUT exon 2 (BRD4-NUT ex15:ex2Δnt1–585). The partial deletion of NUT exon 2 was attributed to a mid-exonic genomic breakpoint and the subsequent activation of a cryptic splice site further downstream within the exon. Inhibition of the canonical 3′ acceptor splice site of NUT intron 1 in cell lines expressing the most common NMC fusion transcripts (PER-403, BRD4-NUT ex11:ex2; PER-624, BRD4-NUT ex15:ex2) induced alternative splicing from the same cryptic splice site as identified in the patient. Detection of low levels of an in-frame BRD4-NUT ex11:ex2Δnt1–585 transcript in PER-403 confirmed endogenous splicing from this alternative exon 2 splice site. Although further studies are necessary to assess the clinical relevance of the increasing number of variant fusions described in NMC, the findings presented in this case identify alternative splicing as a mechanism that contributes to this pathogenic complexity.
Highlights
NUT midline carcinoma (NMC) is a aggressive and fatal form of undifferentiated epithelial cancer affecting both children and adults.[1]
The genetic hallmark of this disease is a rearrangement of chromosome 15 - in the majority of cases fusing the testis-specific nuclear gene NUT to the bromodomain-containing gene bromodomain protein family member 4 (BRD4) on chromosome 19 and thereby creating a new fusion protein that markedly disrupts squamous cell differentiation and promotes oncogenesis.[2,3,4]
Little is known about the functionality of NUT beside its association with the histone acetyltransferase p300, which is thought to contribute to postmeiotic histone hyperacetylation and chromatin compaction in elongating spermatids.[2]
Summary
NUT midline carcinoma (NMC) is a aggressive and fatal form of undifferentiated epithelial cancer affecting both children and adults.[1]. Subsequent Sanger sequencing of the RT–PCR product confirmed that the patient-derived tumor cells expressed a novel in-frame BRD4-NUT fusion transcript with the last 124 nucleotides (nt) of NUT exon 2 fused to BRD4 exon 15 (BRD4-NUT ex15:ex2Δnt[1–585]; Figure 2d).
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