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Tumor Discovery Expert consensus of NUT carcinoma

edema, mucinous appearance, and fibrous changes, often fuses with BRD4, a gene commonly expressed in the cell
accompanied by varying connective tissue proliferation. nucleus. Comparative genomic analyses suggest that the
Neutrophil infiltration may also be observed, occasionally classification, clinical behavior, and treatment strategies
with intraepithelial and stromal lymphocyte infiltration. 42 for NUT carcinoma are best defined by the fusion
partner of NUTM1 rather than by tumor morphology or
4.4.3. IHC markers IHC profile. Evidence indicates that NUT carcinoma is
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Immunohistochemistry in NUT carcinoma can reveal a driven by the NUT fusion oncoprotein, with BRD4 being
range of epithelial markers to varying extents, including the most common fusion partner. Less common fusion
AE1/AE3, epithelial membrane antigen p63, p40, as partners include BRD3::NUTM1 t(15;19)(q14;p34.2),
well as sex-determining region Y-box 2 (SOX2), thyroid NSD3::NUTM1, t(8;15)(p12;q15), and zinc finger protein
transcription factor-1, paired box 8, and MYC. In (ZNF) 532, among others.
addition, other relevant markers such as neuroendocrine The survival rate of NUT carcinoma patients is closely
markers (e.g., synaptophysin, chromogranin, cluster of
differentiation [CD] 56), lymphocyte markers (e.g., CD56, related to the tumor site and the specific fusion partners of
NUTM1, with BRD4 fusion generally associated with the
CD30, CD34, CD43, CD138, and CD45), germ cell tumor poorest prognosis. BRD4 is a member of the BET protein
18
markers (e.g., CD30, placental alkaline phosphatase, family, which includes two bromodomains that bind to
and split-like protein 4), vascular markers (e.g., friend
leukemia integration 1 transcription factor [FLI1] and acetylated histones and an additional C-terminal protein
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CD34), and Ewing’s sarcoma markers (e.g., FLI1 and interaction domain. Bromodomain-containing proteins 2
CD99) can also be expressed in NUT carcinoma. In our (BRD2), BRD3, and BRD4 share sequence homology and
2
analysis, the top positive IHC markers were p63 (43.84%), participate in the transcriptional regulation of numerous
AE1/AE3 (26.65%), p40 (24.36%), CK5/6 (22.92%), and genes involved in cell growth, proliferation, survival, and
CD99 (12.61%). With few exceptions, the NUT protein inflammation. Among these, BRD4 acts as a coactivator in
was expressed in nearly all cases of NUT carcinomas; the transcription of genes involved in the G1 phase of the
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however, it was also widely expressed in other solid tumors. cell cycle (such as MYC, B-cell lymphoma 2 [BCL2], and
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The characteristic diagnostic feature of NUT carcinoma cyclin-dependent kinase 9 [CDK9]). Fusion of NUTM1
is the diffuse nuclear dot-like pattern of NUT staining with BRD2, BRD3, or BRD4 generates chimeric genes that
positivity. 45 encode BRDX-NUTM1 fusion proteins; fusions with other
partner genes (such as NSD3) are collectively referred to as
(a) Recommendation 2 NUT variants. BRD4::NUTM1 typically inhibits cellular
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Apart from surgical specimens, NUT carcinoma tissue differentiation and supports the growth of NUT carcinoma
samples can be obtained through endoscopy, aspiration, cells by binding to acetylated chromatin through its dual
and core-needle biopsy. The histology of NUT carcinoma is bromodomains. It recruits histone acetyltransferase p300 to
often nonspecific, with some cases showing focal squamous enhance wild-type BRD4 activity, markedly increasing the
differentiation accompanied by sudden keratinization and transcription of target genes, thereby activating oncogenes
neutrophil infiltration. IHC staining for NUT typically such as MYC and SOX2. MYC and SOX2 maintain cells
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reveals diffuse nuclear dot-like patterns. While NUT in a relatively undifferentiated, stem-like state, similar to
positivity is a key feature, other IHC markers in NUT cells in NUT carcinomas. Overexpression of oncogenes
carcinoma do not exhibit specificity (level of evidence: such as MYC activates cyclin D1 and cyclin D2, driving the
grade 4; recommendation level: strong recommendation). cell cycle while simultaneously inhibiting p53 activation,
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If the diagnosis remains inconclusive through these which blocks apoptosis and facilitates tumor progression.
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methods, supplementary diagnostic approaches, such such A genetically engineered mouse model of NUT carcinoma
as high-throughput sequencing via blood ctDNA, can be
considered (level of evidence: grade 5; recommendation based on the BRD4::NUTM1 fusion gene closely mirrors
level: strong recommendation). human NUT carcinoma. This model provides strong
evidence that BRD4-NUT alone drives squamous
4.5. Molecular mechanisms and molecular subtypes progenitor cells into a cancerous stage, with BET inhibitors
of NUT carcinoma inducing differentiation and extending survival. 53
The NUTM1 gene on chromosome 15 encodes the In addition, it is important to note that NUT carcinoma
NUT protein, which is usually expressed in testicular is generally considered a rare, undifferentiated squamous
and ovarian germ cells. Chromosomal translocations cell carcinoma, typically characterized by fusion partners
or rearrangements lead to fusion with various partner such as BRD4, BRD3, NSD3, ZNF532, or ZNF592,
genes. In over 70% of NUT carcinoma patients, NUMT1 predominantly affecting the mediastinum or head and
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Volume 3 Issue 4 (2024) 14 doi: 10.36922/td.4904