Abstract
NUT midline carcinoma (NMC) is a rare and aggressive cancer, with survival typically less than seven months, that can arise in people of any age. Genetically, NMC is defined by the chromosomal fusion of NUTM1 with a chromatin-binding partner, typically the bromodomain-containing protein BRD4. However, little is known about other genetic aberrations in this disease. In this study, we used a unique panel of cell lines to describe the molecular-genetic features of NMC. Next-generation sequencing identified a recurring high-impact mutation in the DNA-helicase gene RECQL5 in 75% of lines studied, and biological signals from mutation-signature and network analyses consistent with a general failure in DNA-repair. A high-throughput drug screen confirmed that microtubule inhibitors, topoisomerase inhibitors and anthracyclines are highly cytotoxic in the majority of NMC lines, and that cell lines expressing the BRD4-NUTM1 (exon11:exon2) variant are an order of magnitude more responsive to bromodomain inhibitors (iBETs) on average than those with other BRD4-NUTM1 translocation variants. We also identified a highly significant correlation between iBET and aurora kinase inhibitor efficacy in this study. Integration of exome sequencing, transcriptome, and drug sensitivity profiles suggested that aberrant activity of the nuclear receptor co-activator NCOA3 may correlate with poor response to iBETs. In conclusion, our data emphasize the heterogeneity of NMC and highlights genetic aberrations that could be explored to improve therapeutic strategies. The novel finding of a recurring RECQL5 mutation, together with recent reports of chromoplexy in this disease, suggests that DNA-repair pathways are likely to play a central role in NMC tumorigenesis.
Highlights
NUT midline carcinoma (NMC), known as NUT carcinoma, is an invariably fatal malignancy with an average survival time of less than 7 months [1]
The rarity of NMC significantly limits the availability of tumor material, tumor-derived cell lines provide an invaluable resource for further research
This finding was independently confirmed in another publication whilst conducting this study [34]. The discovery of this NMC cell line languishing in a public repository has two implications: (i) it emphasizes the concept that expression of NUTM1 in an undifferentiated carcinoma is diagnostic for NMC, and (ii) it reinforces the fact that NMC has historically been under-diagnosed, highlighting the potential for further discovery of samples in bio-banks around the world
Summary
NUT midline carcinoma (NMC), known as NUT carcinoma, is an invariably fatal malignancy with an average survival time of less than 7 months [1]. Recent studies have shown that the NUTM1 component of NMC fusion proteins can recruit histone acetyltransferases, such as p300 and CREBbinding protein [4,5,6], whilst the bromodomain moieties of BRD4 (or BRD3) bind to acetylated histones In this way, NUTM1-fusion proteins induce histone hyperacetylation at defined chromatin sites, inactivating genes required for apoptosis and differentiation through the sequestration of p300 [5,6,7,8]. ChIP-Seq data have revealed little overlap in acetylated chromatin domains bound by BRD4-NUTM1 in different NMC samples, with the only consistently affected loci being those of MYC and TP63 [7] In keeping with this observation, knock-down experiments have demonstrated that these two genes are important for maintaining the aggressive phenotype of NMC [7, 9]
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