Demystified molecular pathology of NUT midline … · NMCs to respond to other therapeutic...
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Demystified molecular pathology of NUT midline carcinomas Christopher A French ABSTRACT NUT midline carcinoma (NMC) is a rare, highly lethal cancer that occurs in children and adults of all ages. NMCs uniformly present in the midline, most commonly in the head, neck or mediastinum, as poorly differentiated carcinomas with variable degrees of squamous differentiation. This tumour is defined by rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14. In most cases, NUT is involved in a balanced translocation with the BRD4 gene on chromosome 19p13.1, an event that creates a BRD4eNUT fusion gene. Variant rearrangements, some involving the BRD3 gene, occur in the remaining cases. NMC is diagnosed by detection of NUT rearrangement by fluorescence in situ hybridisation or reverse transcriptase PCR. Due its rarity and lack of characteristic histological features, most cases of NMC currently go unrecognised. NUT MIDLINE CARCINOMA IS DEFINED MOLECULARLY NUT midline carcinoma (NMC) is defined as any malignant epithelial tumour with rearrangement of the nuclear protein in testis (NUT) gene. In approximately two-thirds of cases, NUT (chromo- some 15q14) is fused to BRD4, on chromosome 19p13.1, forming the BRD4eNUT fusion gene (figure 1A,B). 1 In the remaining one-third of cases, the partner gene is BRD3 or other uncharacterised genes; we term these NUT-variant fusion genes (figure 1B). 2 The NUT promoter is active only in adult testis and ciliary ganglion, 12 and as a result only one of the two fusion genes (eg, BRD3eNUT or BRD4eNUT) is expressed. The histological features of NMC (discussed further below) are not distinctive, and diagnosis is based on detection of a NUT rearrangement by either FISH 23 (figure 1C) or reverse transcriptase (RT)-PCR. 4 NUT rear- rangements also appear to be restricted to NMCs, and for this reason the diagnosis is never in ques- tion once rearrangement of NUT has been demon- strated. Presently, clinical research laboratories do not offer molecular tests for NUT rearrangement, and most testing is confined to a handful of research laboratories. Furthermore, awareness of the NMC is only now starting to spread, and there are likely to be hundreds of missed diagnoses yearly. DEMOGRAPHICS NMCs are rare, but their exact frequency is unknown. NMC constituted 7% of a cohort (n¼98 tumours) of poorly differentiated carcinomas occurring in people under the age of 40 years. 3 In a more recent study that was not restricted to young adults and children, NMC made up 18% of poorly differentiated carcinomas of the upper aerodigestive tract, particularly the sinonasal region. 5 Importantly, the average age of patients with NMC in that study was 47 years, overturning the perception that NMCs are largely confined to children and young adults. 3 As indicated in table 1 (a summary of all 22 cases reported to date), the age at presentation ranges from 3 to 78 years, and there is a suggestion of a female predominance (M:F 0.69). The young age at presentation (mean age 25 years) may reflect selection bias generated by clinical patterns of cytogenetic analysis, as karyo- types are obtained frequently on solid tumours in children and rarely on adult carcinomas. CLINICOPATHOLOGICAL FEATURES OF NMCS The clinicopathologicol features of NMCs are summarised in table 1. Most NMCs present in the midline of the upper aerodigestive tract or the mediastinum. The lung is sometimes involved when tumours are large in size, possibly due to secondary extension; there are no proven examples of primary tumours arising in the lung. A few unusual cases have presented below the diaphragm, including tumours that presented in the posterior bladder and the bones of the pelvis, respectively. No cases outside of the midline axis have been reported. With the exception of one case, 6 all patients with NMCs have died (table 1). The mean survival is less than 1 year (9.5 months) despite aggressive chemotherapy and radiation treatment. Most deaths have been caused by local effects of tumour, or complications of treatment. Early data 3 suggested that patients with NUT-variant NMCs survived longer than those with BRD4eNUT rear- rangements (cases 9e11, table 1), but subsequent cases (case 17, table 1, and author ’s unpublished findings) have suggested that there is no difference in survival between these two molecular classes of NMC. The lethality of NMC and the existence of a highly characteristic molecular lesion provide a compelling rationale for attempting to develop therapies that target NUT fusion proteins. The one patient with a BRD4eNUT NMC who has survived 6 is atypical in three respects. First, and most notably, this patient is the sole apparent cure reported among patients with this tumour. Second, the tumour arose within the bones of the pelvis (case 3, table 1); and third, it lacked epithelial differentiation, as judged by electron microscopy and immunohistochemistry (IHC). Based on the absence of epithelial features, the original diagnosis was Ewing sarcoma without EWS rearrangement, and the patient was treated with the Scandinavian Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA Correspondence to Christopher A. French, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA; Cfrench@ partners.org Accepted 21 May 2008 Published Online First 13 June 2008 492 J Clin Pathol 2010;63:492e496. doi:10.1136/jcp.2007.052902 Demystified on 6 September 2018 by guest. Protected by copyright. http://jcp.bmj.com/ J Clin Pathol: first published as 10.1136/jcp.2007.052902 on 13 June 2008. Downloaded from
Transcript of Demystified molecular pathology of NUT midline … · NMCs to respond to other therapeutic...
Demystified molecular pathology of NUTmidline carcinomas
Christopher A French
ABSTRACTNUT midline carcinoma (NMC) is a rare, highly lethalcancer that occurs in children and adults of all ages.NMCs uniformly present in the midline, most commonlyin the head, neck or mediastinum, as poorlydifferentiated carcinomas with variable degrees ofsquamous differentiation. This tumour is defined byrearrangement of the nuclear protein in testis (NUT)gene on chromosome 15q14. In most cases, NUT isinvolved in a balanced translocation with the BRD4 geneon chromosome 19p13.1, an event that createsa BRD4eNUT fusion gene. Variant rearrangements,some involving the BRD3 gene, occur in the remainingcases. NMC is diagnosed by detection of NUTrearrangement by fluorescence in situ hybridisation orreverse transcriptase PCR. Due its rarity and lack ofcharacteristic histological features, most cases of NMCcurrently go unrecognised.
NUT MIDLINE CARCINOMA IS DEFINEDMOLECULARLYNUT midline carcinoma (NMC) is defined as anymalignant epithelial tumour with rearrangement ofthe nuclear protein in testis (NUT) gene. Inapproximately two-thirds of cases, NUT (chromo-some 15q14) is fused to BRD4, on chromosome19p13.1, forming the BRD4eNUT fusion gene(figure 1A,B).1 In the remaining one-third of cases,the partner gene is BRD3 or other uncharacterisedgenes; we term these NUT-variant fusion genes(figure 1B).2 The NUT promoter is active only inadult testis and ciliary ganglion,1 2 and as a resultonly one of the two fusion genes (eg, BRD3eNUTor BRD4eNUT) is expressed. The histologicalfeatures of NMC (discussed further below) are notdistinctive, and diagnosis is based on detection ofa NUT rearrangement by either FISH2 3 (figure 1C)or reverse transcriptase (RT)-PCR.4 NUT rear-rangements also appear to be restricted to NMCs,and for this reason the diagnosis is never in ques-tion once rearrangement of NUT has been demon-strated. Presently, clinical research laboratories donot offer molecular tests for NUT rearrangement,and most testing is confined to a handful ofresearch laboratories. Furthermore, awareness ofthe NMC is only now starting to spread, andthere are likely to be hundreds of missed diagnosesyearly.
DEMOGRAPHICSNMCs are rare, but their exact frequency isunknown. NMC constituted 7% of a cohort (n¼98tumours) of poorly differentiated carcinomasoccurring in people under the age of 40 years.3 Ina more recent study that was not restricted to
young adults and children, NMC made up 18% ofpoorly differentiated carcinomas of the upperaerodigestive tract, particularly the sinonasalregion.5 Importantly, the average age of patientswith NMC in that study was 47 years, overturningthe perception that NMCs are largely confined tochildren and young adults.3 As indicated in table 1(a summary of all 22 cases reported to date), the ageat presentation ranges from 3 to 78 years, and thereis a suggestion of a female predominance (M:F0.69). The young age at presentation (mean age25 years) may reflect selection bias generated byclinical patterns of cytogenetic analysis, as karyo-types are obtained frequently on solid tumours inchildren and rarely on adult carcinomas.
CLINICOPATHOLOGICAL FEATURES OF NMCSThe clinicopathologicol features of NMCs aresummarised in table 1. Most NMCs present in themidline of the upper aerodigestive tract or themediastinum. The lung is sometimes involvedwhen tumours are large in size, possibly due tosecondary extension; there are no proven examplesof primary tumours arising in the lung. A fewunusual cases have presented below the diaphragm,including tumours that presented in the posteriorbladder and the bones of the pelvis, respectively. Nocases outside of the midline axis have beenreported.With the exception of one case,6 all patients with
NMCs have died (table 1). The mean survival is lessthan 1 year (9.5 months) despite aggressivechemotherapy and radiation treatment. Mostdeaths have been caused by local effects of tumour,or complications of treatment. Early data3
suggested that patients with NUT-variant NMCssurvived longer than those with BRD4eNUT rear-rangements (cases 9e11, table 1), but subsequentcases (case 17, table 1, and author ’s unpublishedfindings) have suggested that there is no differencein survival between these two molecular classes ofNMC. The lethality of NMC and the existence ofa highly characteristic molecular lesion providea compelling rationale for attempting to developtherapies that target NUT fusion proteins.The one patient with a BRD4eNUT NMC who
has survived6 is atypical in three respects. First, andmost notably, this patient is the sole apparent curereported among patients with this tumour. Second,the tumour arose within the bones of the pelvis(case 3, table 1); and third, it lacked epithelialdifferentiation, as judged by electron microscopyand immunohistochemistry (IHC). Based on theabsence of epithelial features, the original diagnosiswas Ewing sarcoma without EWS rearrangement,and the patient was treated with the Scandinavian
Department of Pathology,Brigham and Women’s Hospital,Harvard Medical School,Boston, Massachusetts, USA
Correspondence toChristopher A. French,Department of Pathology,Brigham and Women’s Hospital,75 Francis Street, Boston, MA02115, USA; [email protected]
Accepted 21 May 2008Published Online First13 June 2008
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Sarcoma Group (SSG) IX protocol for inoperable Ewingsarcoma. Based on this anecdotal evidence and the failure ofNMCs to respond to other therapeutic regimens, severalpatients with NMC have been treated with Ewing sarcomaprotocols subsequently4 (author ’s unpublished observations),but all have succumbed to their disease. It thus seems likelythat the fortunate outcome in the one survivor of NMC was
due to the unusual characteristics of the tumour, and not dueto fortuitous treatment with a regimen that is generallyeffective in NMC.
CELL OF ORIGINNMCs were initially thought to be derived exclusively fromthymus,7 based on the first three reported cases,8e10 but
Table 1 Clinical characteristics of reported NUT midline carcinomas
Case no. Age (years) Sex Location Diagnosis Survival (months) BRD4eNUT NUT-variant Reference
1 3 M Bladder PDSQC 8.5 Yes e French et al3
2 5 M Mediastinum Mucoepidermoid carcinoma 3.5 Yes e Lee et al9
3 10 M Iliac bone Ewing sarcoma/PNET AW/OD 180 Yes e Dang et al18
4 11 F Thorax Undifferentiated carcinoma 4.5 Yes e Kees et al8
5 12 F Nasopharynx PDSQC 3.25 Yes e Vargas et al11; French et al19
6 13 F Epiglottis Undifferentiated carcinoma 9 Yes e Vargas et al11
7 15 M Mediastinum Thymic PDSQC 6 Yes e Toretsky et al12
8 15 F Orbit PDSQC 7 Yes e French et al3
9 16 M Lung SQC 37 e Yes French et al3
10 16 F Trachea PD carcinoma 31.5 e Yes French et al3
11 21 F Nasopharynx Nasopharyngeal carcinoma 10.25 e Yes French et al3
12 22 F Thymus PD carcinoma 3.5 Yes e Kubonishi et al10
13 26 M Sinonasal Undifferentiated carcinoma 16.75 Yes e French et al3
14 30 F Mediastinum PD carcinoma 3.25 Yes e Engleson et al4
15 31 M Nasal cavity SNUC Yes e
16 34 F Thorax NK NK Yes e Dang et al18
17 34 M Mediastinum PD carcinoma 2 e Yes French et al2
18 35 F Mediastinum PD carcinoma 2 Yes e French et al3
19 39 F Nasal cavity and sinus PDSQC Yes e
20 40 F Nasal cavity and sinus PDSQC Yes e
21 47 M Nasal cavity and sinus SNUC Yes e
22 78 F Supraglottic larynx Undifferentiated carcinoma Yes e
Mean 25.14 9.53
AW/OD, alive without disease; NK, not known; PD carcinoma, poorly differentiated carcinoma; PDSQC, poorly differentiated squamous cell carcinoma; PNET, primitive neuroectodermal tumour;SNUC, sinonasal undifferentiated carcinoma; SQC, squamous cell carcinoma.
Figure 1 Translocations of thenuclear protein in testis (NUT) gene arepathognomonic of NUT midlinecarcinomas (NMCs). (A) Karyotype ofa patient with BRD4eNUT NMC isremarkably simple, and revealsa reciprocal translocation betweenNUT, on 15q14, and BRD4, on 19p13.1(t(15;19)(q14;p13.1)). Red and greendots illustrate where split-apartfluorescence in situ hybridisation (FISH)probes flanking NUT (green, telomericto NUT; red, centromeric to NUT) canbe used for diagnostic FISH (as seen in(C)). (B) Schematic of the fusiononcogenes formed when NUT istranslocated to BRD3 and BRD4 loci(adapted from French et al2) revealsthat the predicted oncoproteins containboth bromodomains and the extraterminal domain of BRD3/BRD4, andnearly the entirety of NUT. (C)Diagnosis of a NMC can be made usinga dual-colour FISH split-apart assay ofdifferentially labelled probes flankingthe NUT gene (see (A) above) onformalin-fixed paraffin sections oftumour (adapted from French et al2).
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numerous non-thymic tumours, including tumours arisingbelow the diaphragm, have been reported subsequently. Becauseof the frequent involvement of midline structures in the head,neck, mediastinal and other midline structures, we speculatethat NMCs arise from primitive neural crest-derived cells. This isin line with the absence of any in situ component whentumours involve epithelium-lined organs (eg, trachea orepiglottis), and it is also consistent with expression profilingresults, which show the highest level of expression in the adultciliary ganglion (BioGPS, http://biogps.gnf.org/), a neural-crest-derived structure.
PATHOGENESISAs is true of most other translocations associated with specifichuman cancers, the basis for the genesis of NUT rearrangementsis unknown. There are no known associations with exposures toenvironmental toxins or infectious agents, smoking, or onco-genic viruses such as human papillomavirus or EpsteineBarrvirus5 (Stelow et al5 and author ’s unpublished observations).Transforming activity by NUT-fusion proteins has not beendemonstrated directly, but all karyotypes thus far obtained havebeen remarkably simple (figure 1A), often having the t(15;19) asthe sole aberration.4 6 8e12 By analogy to other cancers associ-ated with chromosomal translocations and simple karyotypes(such as acute leukaemias), this association suggests that NUTrearrangement is a very early, possibly tumour-initiating, event.
The normal function of BRD4 is beginning to be elucidated.BRD4 was originally named mitotic-chromosome-associatedprotein for its unique property of remaining bound to chro-
matin, via its two bromodomains, during mitosis.13 By means ofits mitotic-chromosome binding, BRD4 is hypothesised to markactively transcribed genes before mitosis, thus providing a kindof cellular memory that ensures re-initiation of transcriptionfrom these sites after mitosis is completed. Two recent studieshave provided evidence that this may indeed be the case. Byrecruiting cdk9 (a component of the P-TEFb transcription elon-gation complex) and RNA polymerase II to chromatin duringlate mitosis, BRD4 initiates the transcription of G1 genes.14 15
The function of BRD3 is less characterised but, like all proteinsin the BRD family, it also contains two acetyl-histone-bindingbromodomains and the obscure extra terminal domain.16 17
BRD3 is highly homologous to BRD4 (figure 1A), and so itsinvolvement in NMCs is no surprise.In contrast to BRD proteins, NUT is likely to be unstructured
and lacks known functional domains. Further, unlike the BRDproteins, NUT is poorly conserved and apparently restricted tomammals, as no homologue has been identified in lower verte-brates. For these reasons, little is currently known about NUT.Unlike BRD4, NUT normally shuttles between the nucleus andcytoplasm, but it remains bound to chromatin when fused toBRD4 or BRD3.2 This has led to the hypothesis that the BRDprotein moiety in the fusion proteins serves to tether NUT tochromatin, thus modifying the function of either or bothproteins in a way that affects transcription. One importantconsequence of BRDeNUT expression has been discovered byusing siRNA to knock down the expression of BRD3eNUT orBRD4eNUT in NMC cell lines. Withdrawal of the NUT fusionproteins resulted in a dramatic and irreversible squamous
Figure 2 BRD4eNUT blocksdifferentiation. (A) 72 h after negativecontrol siRNA transfection of theBRD4eNUT-expressing cell line TC-797, the cells remain undifferentiatedand unchanged (bar 50 mm) (adaptedfrom French et al2). (B) After siRNA-induced BRD4eNUT knockdown, theTC-797 cells display dramaticsquamous differentiation, withstratification and enlargement of cells(adapted from French et al2). (C)3 weeks after siRNA knockdown,TC-797 cells resemble benign,parakeratotic squamous epithelium,with flattening of cells, andcondensation of their nuclei.
Table 2 Morphological mimics of NUT midline carcinoma
Tumour Monomorphic Distinguishing marker*
Basaloid squamous cell carcinoma � Human papillomavirus20e22
Ewings/primitive neuroectodermal tumour +
Extragonadal germ cell tumour + PLAP, Oct 3/4, b-HCGLymphoma/leukaemia + Leucocyte common antigen
Nasopharyngeal carcinoma + EpsteineBarr virus
Non-NMC PDSQC �Olfactory neuroblastoma + Synaptophysin
Poorly differentiated carcinoma �Small cell carcinoma +
SNUC +
*All the markers are negative in NMCs (French CA et al3 and author’s unpublished observations).b-HCG, b human chorionic gonadotrophin; NMC, NUT midline carcinoma; PDSQC, poorly differentiated squamous cell carcinoma; PLAP,placental-like alkaline phosphatase; SNUC, sinonasal undifferentiated carcinoma.
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differentiation and arrested growth (figure 2). These findings,which are reminiscent of the effects of retinoic acid on thedifferentiation of acute promyelocytic leukaemia cells expressingPMLeRARa fusion proteins, demonstrate that BRDeNUTproteins block differentiation.18 The dramatic phenotypeproduced by BRDeNUT knockdown offers an excellent readoutfor high-throughput screens of drugs that interfere withBRDeNUT fusion protein functions.
DIAGNOSISThe diagnosis of NMC is made definitively by demonstration ofNUT rearrangement by fluorescence in situ hybridisation (FISH)
(figure 1C) or by demonstration of a BRD4eNUT fusion tran-script by RT-PCR.4 FISH is preferred because it will detect allNMCs, including all NUT variants, whereas RT-PCR cancurrently only detect BRD3eNUT or BRD4eNUT tumours. Thechallenge is not the diagnosis of NMC, but to determine whento perform the test, which is not yet available in clinical labo-ratories.If NMC is not to be missed, any poorly differentiated,
monomorphic, midline neoplasm that does not stain for lineage-specific markers should be considered for NUT-rearrangementtesting (table 2, figure 3AeG). This group includes sinonasalundifferentiated carcinomas5 and any poorly differentiated
Figure 3 NUT midline carcinomas(NMCs) are monomorphic, poorlydifferentiated carcinomas with varyingdegrees of squamous differentiation.(A, B) NMCs can mimic otherundifferentiated neoplasms such asgerm cell tumours, Ewing sarcoma orlymphoma. (C, D) Abrupt squamousdifferentiation is characteristic of someNMCs. (E, F) NUT-variant NMCs looksimilar to BRD4eNUT tumours. (G)Rarely, there can be extensivesquamous differentiation. (H, I) Poorlydifferentiated, non-NMCs often displaypleomorphism and atypia that isuncharacteristic of NMCs.
Figure 4 NUT polyclonal antibody stains testis and NUT midline carcinoma (NMC). (A) The spermatogonia and maturing spermatocytes, but notsperm, of testis produce NUT. Diffuse nuclear reactivity with NUT antibody is seen in (B), a BRD4eNUT tumour, (C, D) two BRD3eNUT tumours, and(EeG) three uncharacterised NUT-variant tumours, (H) but not in this squamous cell carcinoma without NUT rearrangement. (D, inset) A specklednuclear pattern of NUT antibody staining is characteristic of NMCs. (BeH) Adapted from French et al.2
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carcinoma, with or without squamous differentiation, whosecells lack the pronounced atypia and pleomorphism character-istic of garden variety poorly differentiated carcinomas (figure3H, I). Focal squamous differentiation is common in NMCs(figure 3C, D, F), and may occasionally be extensive (figure 3G).A curious, characteristic finding is focal abrupt squamousdifferentiation (figure 3C, D), where stratification and gradualdifferentiation are absent. To our knowledge, abrupt squamousdifferentiation, while common in NMCs, is rarely seen in othercarcinomas.
As is the case for certain other oncoproteins, such as cyclin D1and anaplastic lymphoma kinase, that are mis-expressed due tochromosomal translocations, it is possible that IHC tests forNUTwill prove to be valuable aids in the diagnosis of NMC. Asstated, normal NUTexpression is restricted almost exclusively tothe testis (figure 4A). Thus, positive nuclear IHC staining forNUT in tissue outside the testis is indicative of aberrantexpression, such as in NMCs, where both BRD4eNUT andNUT-variants localise to the nucleus (figure 4BeG).2 We havetested our own non-commercial rabbit polyclonal NUT anti-bodies for diagnostic utility using a panel of five NMCs and 23NUT-unrelated poorly differentiation carcinomas of the upperaerodigestive tract.5 We found that our NUT antibody hasa specificity of 95% and a sensitivity of 60%, indicating that it fallsshort of the sensitivity one would like in a diagnostic test that isenvisioned as a screen for the selection of tumours for confirma-tory FISH testing. It is hoped that NUT monoclonal antibodies,which are currently being evaluated, will permit the developmentof a more sensitive IHC-based diagnostic screening test.
Acknowledgements I would like to thank Dr Jon C Aster MD PhD for hiscomments and suggestions.
Funding The work reported here was supported by the National Cancer InstituteMentored Clinical Scientist Award (KO8 CA92158).
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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mechanism in aggressive carcinoma. Cancer Res 2003;63:304e7.2. French CA, Ramirez CL, Kolmakova J, et al. BRDeNUT oncoproteins: a family of
closely related nuclear proteins that block epithelial differentiation and maintain thegrowth of carcinoma cells. Oncogene 2008;27:2237e42.
3. French CA, Kutok JL, Faquin WC, et al. Midline carcinoma of children and youngadults with NUT rearrangement. J Clin Oncol 2004;22:4135e9.
4. Engleson J, Soller M, Panagopoulos I, et al. Midline carcinoma with t(15;19) andBRD4eNUT fusion oncogene in a 30-year-old female with response to docetaxel andradiotherapy. BMC Cancer 2006;6:69.
5. Stelow EB BA, Bellizzi AM, Taneja K, et al. NUT rearrangement in undifferentiatedcarcinomas of the upper aerodigestive tract. Am J Surg Pathol 2008;32:828e34.
6. Mertens F, Wiebe T, Adlercreutz C, et al. Successful treatment of a child with t(15;19)-positive tumour. Pediatr Blood Cancer 2007;49:1015e17.
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8. Kees UR, Mulcahy MT, Willoughby ML. Intrathoracic carcinoma in an 11-year-old girlshowing a translocation t(15;19). Am J Pediatr Hematol Oncol 1991;13:459e64.
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12. Toretsky JA, Jenson J, Sun CC, et al. Translocation (11;15;19): a highly specificchromosome rearrangement associated with poorly differentiated thymic carcinomain young patients. Am J Clin Oncol 2003;26:300e6.
13. Dey A, Ellenberg J, Farina A, et al. A bromodomain protein, MCAP, associates withmitotic chromosomes and affects G(2)-to-M transition. Mol Cell Biol2000;20:6537e49.
14. Yang Z, He N, Zhou Q. Brd4 recruits P-TEFb to chromosomes at late mitosis topromote G1 gene expression and cell cycle progression. Mol Cell Biol2008;28:967e76.
15. Mochizuki K, Nishiyama A, Jang MK, et al. The bromodomain protein Brd4 stimulatesG1 gene transcription and promotes progression to S phase. J Biol Chem2008;283:9040e8.
16. Wu SY, Chiang CM. The double bromodomain-containing chromatin adaptor Brd4and transcriptional regulation. J Biol Chem 2007;282:13141e5.
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Take-home messages
< NMC is an aggressive carcinoma genetically defined byrearrangement of NUT.
< NMC is likely vastly under-recognized and under-diagnosed.< Most NMCs are squamous cell carcinomas and can only be
identified by molecular or immunohistochemical testing.< The diagnosis of NMC should be considered in any non-
smoking patient with poorly differentiated squamous cellcarcinoma.
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