NUT carcinoma (midline carcinoma with NUTM1 rearrangement)
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.
Overview
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.
State of the art today
- 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.
- BET inhibitors have shown objective responses, but durability is limited; degraders and combinations are the next step.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Registry data show that complete resection and radiotherapy of localised disease produce long-term survivors, so the disease is not uniformly fatal.
Where it starts and where it drains
Site decides cause and behaviour: HPV drives oropharyngeal cancer, EBV drives nasopharyngeal cancer, tobacco drives oral and laryngeal cancer; all drain into the neck node levels that surgeons and radiotherapists map.
- Oral cavity and tongue
- Oropharynx: tonsil, base of tongue (HPV)
- Nasopharynx (EBV)BRD4-NUTM1 (most common) · BRD3-NUTM1 · NSD3-NUTM1 · Other NUTM1 partners (ZNF532, ZNF592)
- Larynx and hypopharynx
- Parotid and other salivary glands
- Thyroid
- level I (submandibular)
- level II (upper jugular)
- level III-IV (jugular)
- level V (posterior)
- level VI (central, thyroid)
- retropharyngeal (nasopharynx)
Same organ: Head and neck squamous cell carcinoma, Nasopharyngeal carcinoma, Salivary gland cancers, Thyroid cancer, Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma), Parathyroid carcinoma, Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)
Very rare and under-recognised; arises at any age with a median in the twenties, most often in the head, neck and thorax.
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
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.
Clinical trial of a BET inhibitor (ZEN-3694, NUV-868, molibresib) alone or with chemotherapy; palliative chemotherapy and radiotherapy.
Subtypes & biomarkers
top- BRD4-NUTM1 (most common)
- BRD3-NUTM1
- NSD3-NUTM1
- Other NUTM1 partners (ZNF532, ZNF592)
- 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)
Target prevalence in this cancer
- 1991First reports of aggressive midline carcinoma with t(15;19) in children
- 2003BRD4-NUT fusion cloned
French and colleagues identify the fusion gene.
- 2009NUT immunohistochemistry validated
Haack and colleagues: highly specific antibody enables diagnosis.
- 2010BET inhibitor JQ1 induces differentiation of NUT carcinoma cells
Filippakopoulos and colleagues, Nature: proof of concept for BET inhibition.
- 2016First BET inhibitor responses in patients
Birabresib (OTX015) and molibresib phase 1 cohorts.
- 2021International NUT Carcinoma Registry outcomes
Chau and colleagues, JCO: fusion partner and initial treatment predict survival.
Open problems, and what is being done about each
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.
and how the field plans to fix it →What is being done about thisRare cancers and small trialsAvailable now- AI trial matching & clinical decision supportEstablished
- Comprehensive genomic profilingStandard of care
- Dinutuximab (ch14.18) / dinutuximab betaApproved
- Eflornithine (DFMO)Approved
- LarotrectinibApproved
- Limb-salvage surgery and endoprosthetic reconstructionStandard of care
In trials- ACTIONRecruiting
- COG AALL1731Positive
- COG ANBL0032Positive
- DeFiPositive
- Euro Ewing 2012Positive
- Functional (ex vivo) drug testingEmerging
Ideas and roadmaps- A digital second-opinion network answering community oncologists within 72 hours
- A DRUP-style protocol for off-label generic targeted drugs in rare tumours
- A funded expert second opinion for every new high-stakes or rare cancer diagnosis
- A global first-in-human network for academic cancer trials with single ethics review
- A global open trials operating system any hospital can plug into
- A live 'seats available' feed for trial slots, like airline inventory
Background: Basket, umbrella, and platform trials, Centralisation and high-volume centres, FNCLCC grade (soft-tissue sarcoma), Histotype-tailored therapy, INRG staging and risk groups. Also on OnCo: Find a trial · Expert centres.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Expert centres
topCentres linked to this cancer in OnCo
- via this cancer
- Aarhus University HospitalAarhus, DKvia IMRT / IGRT (modern external beam)
- American Society for Radiation OncologyArlington, VA, USvia IMRT / IGRT (modern external beam)
- Centre Antoine LacassagneNice, FRvia IMRT / IGRT (modern external beam)
- Centre Oscar LambretLille, FRvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Comprehensive Cancer Center Freiburg (CCCF)Freiburg im Breisgau, DEvia IMRT / IGRT (modern external beam)
- European Society for Radiotherapy and OncologyBrussels, BEvia IMRT / IGRT (modern external beam)
- Geneva University Hospitals (HUG)Geneva, CHvia IMRT / IGRT (modern external beam)
- Groote Schuur Hospital / University of Cape TownCape Town, ZAvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Hacettepe University Cancer InstituteAnkara, TRvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Ho Chi Minh City Oncology HospitalHo Chi Minh City, VNvia IMRT / IGRT (modern external beam)
- Hokkaido University HospitalSapporo, JPvia IMRT / IGRT (modern external beam)
- Hunan Cancer HospitalChangsha, CNvia IMRT / IGRT (modern external beam)
- Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolis, IN, USNCI comprehensivevia Cisplatin
- Institut BergoniéBordeaux, FRvia IMRT / IGRT (modern external beam)
- Institut National d'Oncologie, RabatRabat, MAvia IMRT / IGRT (modern external beam)
- Institut Salah AzaïezTunis, TNvia IMRT / IGRT (modern external beam)
- Institute of Oncology LjubljanaLjubljana, SIvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- International Extranodal Lymphoma Study GroupBellinzona, CHvia IMRT / IGRT (modern external beam)
- IRCCS Humanitas Research HospitalRozzano (Milan), ITvia IMRT / IGRT (modern external beam)
- Istanbul University Institute of OncologyIstanbul, TRvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Juravinski Cancer Centre / Escarpment Cancer Research InstituteHamilton, ON, CAvia IMRT / IGRT (modern external beam)
- Kenyatta National HospitalNairobi, KEvia IMRT / IGRT (modern external beam)
- Korle Bu Teaching HospitalAccra, GHvia IMRT / IGRT (modern external beam)
- Lagos University Teaching HospitalLagos, NGvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- National Institute of Oncology, HungaryBudapest, HUvia IMRT / IGRT (modern external beam)
- via Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)
- via IMRT / IGRT (modern external beam)
- Ocean Road Cancer InstituteDar es Salaam, TZvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Rajiv Gandhi Cancer Institute and Research CentreNew Delhi, INvia IMRT / IGRT (modern external beam)
- Rambam Health Care CampusHaifa, ILvia IMRT / IGRT (modern external beam)
- Rigshospitalet – Copenhagen University HospitalCopenhagen, DKvia IMRT / IGRT (modern external beam)
- Royal Adelaide HospitalAdelaide, AUvia IMRT / IGRT (modern external beam)
- Ruijin Hospital, Shanghai Jiao Tong UniversityShanghai, CNvia Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)
- via IMRT / IGRT (modern external beam)
- Siriraj Hospital, Mahidol UniversityBangkok, THvia IMRT / IGRT (modern external beam)
- Tata Medical Center, KolkataKolkata, INvia IMRT / IGRT (modern external beam)
- Tawam HospitalAl Ain, AEvia IMRT / IGRT (modern external beam)
- Tel Aviv Sourasky Medical CenterTel Aviv, ILvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- TROG Cancer ResearchNewcastle, NSW, AUvia IMRT / IGRT (modern external beam)
- UMC Utrecht Cancer CenterUtrecht, NLvia IMRT / IGRT (modern external beam)
- University of Malaya Medical CentreKuala Lumpur, MYvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)
- Velindre Cancer CentreCardiff, GBvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Zhejiang Cancer HospitalHangzhou, CNvia IMRT / IGRT (modern external beam)
Questions to ask
topQuestions to ask your oncologist about NUT carcinoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example NUT immunohistochemistry, NUTM1 fusion by FISH or RNA sequencing, Fusion partner, Site), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include BRD4-NUTM1, BRD3-NUTM1, NSD3-NUTM1.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Localised
- For my situation (localised), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Ifosfamide, Cisplatin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Advanced or relapsed
- For my situation (advanced or relapsed), which of the standard options do you recommend and why?Why: Guideline options include: Clinical trial of a BET inhibitor (ZEN-3694, NUV-868, molibresib) alone or with chemotherapy; palliative chemotherapy and radiotherapy.
Any stage
- Are there clinical trials I could join, for example of Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Misdiagnosis and delay: NUT immunohistochemistry should be routine in poorly differentiated midline tumours”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “BET inhibitor responses are short: degraders, CDK9 and HDAC combinations, and chemotherapy combinations are in trials”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
6targets
1drugs
3institutions
1pathways
3terms
2bottlenecks
2Latest papers
topQuery for this cancer: (TITLE:"NUT carcinoma" OR ABSTRACT:"NUT carcinoma" OR TITLE:"midline carcinoma with NUTM1 rearrangement" OR ABSTRACT:"midline carcinoma with NUTM1 rearrangement" OR TITLE:"NUT midline carcinoma" OR ABSTRACT:"NUT midline carcinoma" OR TITLE:"Midline tract carcinoma with NUT gene changes" OR ABSTRACT:"Midline tract carcinoma with NUT gene changes" OR TITLE:"NMC" OR ABSTRACT:"NMC") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about NUT carcinoma (midline carcinoma with NUTM1 rearrangement), not a curated reading list.
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