# NUT carcinoma (midline carcinoma with NUTM1 rearrangement)

Source: https://onco.cc/cancers/nut-carcinoma/  
OnCo record `nut-carcinoma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

NUT carcinoma is a fast-growing cancer of the midline of the body driven by a single fused gene, BRD4-NUTM1, that locks cells in an immature state. Chemotherapy and surgery rarely control it for long, but drugs that block the BET proteins the fusion depends on have produced responses and are the focus of trials.

## Summary

NUT carcinoma is a poorly differentiated squamous carcinoma defined by rearrangement of NUTM1 (nuclear protein in testis), most often fused to BRD4 (about 70 percent), otherwise BRD3, NSD3 or ZNF532. The fusion protein tethers NUT's histone acetyltransferase-recruiting domain to BET bromodomains, creating megadomains of hyperacetylated chromatin that drive MYC and SOX2 expression and block squamous differentiation. It was first recognised in the mediastinum of children and young adults but occurs at any age and in the sinonasal tract, lung, and other sites; diagnosis requires NUT immunohistochemistry (highly specific) or fusion testing, and many cases were historically misdiagnosed as undifferentiated carcinoma or sarcoma.

The disease is among the most aggressive human cancers. Multimodality treatment (surgery, radiotherapy and ifosfamide- or platinum-based chemotherapy, Ewing-type regimens) achieves control in a minority, mostly those with localised disease amenable to complete resection and radiotherapy. The International NUT Carcinoma Registry (Brigham and Women's Hospital) has pooled outcomes and shown that initial resection or radiotherapy is associated with longer survival, and that non-BRD4 fusions have a somewhat better course.

Mechanistically the disease is an ideal test of BET inhibition: BRD4-NUTM1 requires bromodomain binding to chromatin. BET inhibitors (molibresib/GSK525762, birabresib/OTX015, ZEN-3694, NUV-868) have produced objective responses and disease stabilisation in NUT carcinoma cohorts of phase 1 and 2 trials, with thrombocytopenia as the dose-limiting toxicity; combination with chemotherapy, CDK9 or HDAC inhibitors, and next-generation BET degraders are the main directions. Rapid, accurate diagnosis is the first intervention that changes outcome.

## Fields

- Kind: Cancer
- Last checked: 2026-09-10
- Also known as: NUT midline carcinoma; Midline tract carcinoma with NUT gene changes; NMC
- Tags: nci-coverage; rare; head-and-neck; paediatric
- Group: head and neck
- Burden: Very rare and under-recognised; arises at any age with a median in the twenties, most often in the head, neck and thorax.
- Subtypes: BRD4-NUTM1 (most common); BRD3-NUTM1; NSD3-NUTM1; Other NUTM1 partners (ZNF532, ZNF592)
- Biomarkers: NUT immunohistochemistry (C52 antibody, nuclear speckled); NUTM1 fusion by FISH or RNA sequencing; Fusion partner (non-BRD4 partners associated with longer survival in the registry); Site (thoracic vs non-thoracic)

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/nut-carcinoma/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/nut-carcinoma/#overview [4 state-of-the-art points]
- What it is (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/nut-carcinoma/#what-it-is [4 subtypes]
- Finding it (on the hub): How it shows itself, how it is confirmed, what screening exists, and the biomarkers clinicians test for. https://onco.cc/cancers/nut-carcinoma/#finding-it [4 biomarkers]
- Treating it (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/nut-carcinoma/#treating-it [2 settings, 1 decision with options]
- Evidence (on the hub): Trials recruiting now, the landmark trials, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/nut-carcinoma/#evidence [3 trials, 1 key paper, 6 milestones]
- The science (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/nut-carcinoma/#science [2 targets, 3 pathways]
- Where you are (own page): Cases by country, the UK and NHS pathway and other country lenses, and the expert centres with trials on record. https://onco.cc/cancers/nut-carcinoma/where-you-are/ [1 centre]
- Living with it (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/nut-carcinoma/#living-with-it [12 questions, 2 red cards]
- What is coming (own page): Everything in development, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/nut-carcinoma/coming/ [4 medicines, 3 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/nut-carcinoma/data/ [27 connected records]

## Standard of care

- Localised: Multimodality: complete resection where feasible, radiotherapy, and intensive chemotherapy (ifosfamide-based or platinum-based, often Ewing-type regimens); early referral to a centre with NUT carcinoma experience. ([Ifosfamide](https://onco.cc/drugs/ifosfamide/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- Advanced or relapsed: Clinical trial of a BET inhibitor (ZEN-3694, NUV-868, molibresib) alone or with chemotherapy; palliative chemotherapy and radiotherapy. ([Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/))

## State of the art

- A single oncogenic fusion with a druggable domain: NUT carcinoma is the founding indication for BET bromodomain inhibitors.
- NUT immunohistochemistry has made diagnosis fast and cheap, and is now recommended for any poorly differentiated midline carcinoma, particularly in young patients.
- Registry data show that complete resection and radiotherapy of localised disease produce long-term survivors, so the disease is not uniformly fatal.
- BET inhibitors have shown objective responses, but durability is limited; degraders and combinations are the next step.

## Open problems

- Misdiagnosis and delay: NUT immunohistochemistry should be routine in poorly differentiated midline tumours.
- BET inhibitor responses are short: degraders, CDK9 and HDAC combinations, and chemotherapy combinations are in trials.
- Thrombocytopenia limits BET inhibitor dosing.
- No randomised trials exist; the registry is the evidence base.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/NUT_midline_carcinoma
- NCI PDQ: childhood midline tract carcinoma with NUT gene changes: https://www.cancer.gov/types/midline/patient-child-midline-tract-carcinoma-treatment-pdq
- Filippakopoulos 2010: BET inhibition in NUT carcinoma (Nature): https://doi.org/10.1038/nature09504

## Connected records

- technologies: [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/)
- drugs: [Cisplatin](https://onco.cc/drugs/cisplatin/), [Etoposide](https://onco.cc/drugs/etoposide/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/), [ZEN-3694](https://onco.cc/drugs/zen-3694/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [MYC](https://onco.cc/pathways/myc/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)
- terms: [Gene fusion](https://onco.cc/terms/gene-fusion/), [Rare cancers](https://onco.cc/terms/rare-cancers/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Selective inhibition of BET bromodomains](https://onco.cc/key-papers/paper-filippakopoulos-nature/)
- trials: [Cemiplimab in metastatic or unresectable NUT carcinoma (Northwestern pilot)](https://onco.cc/trials/cemiplimab-nut/), [ZEN-3694 with abemaciclib in NUT carcinoma, breast cancer and other solid tumours (NCI phase 1)](https://onco.cc/trials/zen-3694-abemaciclib-nut/), [ZEN-3694 with platinum chemotherapy in NUT carcinoma (NCI phase 1/2)](https://onco.cc/trials/zen-3694-platinum-nut/)
- cancers: [Esthesioneuroblastoma (olfactory neuroblastoma)](https://onco.cc/cancers/esthesioneuroblastoma/), [Rare cancers of childhood (NCI PDQ umbrella)](https://onco.cc/cancers/rare-childhood-cancers/), [Sinonasal undifferentiated carcinoma (SNUC) and SWI/SNF-deficient sinonasal carcinoma](https://onco.cc/cancers/sinonasal-undifferentiated-carcinoma/)
- targets: [BRD4](https://onco.cc/targets/brd4/)

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JSON: https://onco.cc/api/v1/entities/nut-carcinoma.json