NUT Carcinoma: Clinicopathologic Features, Molecular Genetics and Epigenetics

Abstract

Nuclear protein in testis (NUT) carcinoma is a rare, highly aggressive, poorly differentiated carcinoma occurring mostly in adolescents and young adults. This tumor usually arises from the midline structures of the thorax, head, and neck, and exhibits variable degrees of squamous differentiation. NUT carcinoma is defined by the presence of a NUTM1 (15q14) rearrangement with multiple other genes. In about 70-80% of the cases, NUTM1 is involved in a balanced translocation with the BRD4 gene (19p13.12), leading to a BRD4-NUTM1 fusion oncogene. Other variant rearrangements include BRD3-NUTM1 fusion (~15-20%) and NSD3-NUTM1 fusion (~6%), among others. The diagnosis of NUT carcinoma requires the detection of nuclear expression of the NUT protein by immunohistochemistry. Additional methods for diagnosis include the detection of a NUTM1 rearrangement by fluorescence in situ hybridization or by reverse transcriptase PCR. NUT carcinoma is usually underrecognized due to its rarity and lack of characteristic histological features. Therefore, the goal of this review is to provide relevant recent information regarding the clinicopathologic features of NUT carcinoma, the role of the multiple NUTM1 gene rearrangements in carcinogenesis, and the impact of understanding these underlying molecular mechanisms that may result in the development of possible novel targeted therapies.

Keywords: BET inhibitors; BRD-NUTM1; HDAC inhibitors; NSD3; NUT carcinoma; NUT midline carcinoma; zinc finger proteins.

Figure 1

Histomorphology of NUT carcinoma and diagnosis by immunohistochemistry. (A) Diffuse sheets of poorly differentiated monotonous round cells with focal necrosis (top right). (B) Areas with abrupt keratinization in NC can be seen in up to 30% of cases. (C) Focal cytoplasmic clearing and intratumoral neutrophilic inflammatory infiltrate. (D) NUT immunohistochemical stain (monoclonal antibody, clone C52) shows diffuse nuclear labeling, often with a speckled pattern. Same case from panel (B).

Figure 2

Schematic of NUTM1 fusions with BRD3, BRD4, NSD3, ZNF532, and ZNF592 and respective wild-type proteins (arrowheads denote fusion breakpoints). The most common of these fusions is BRD4-NUTM1 comprising about 70-80% of all cases. [N, amino- or N-terminal; NLS, nuclear localization signal; NES, nuclear export signal; BD, bromodomains (BD1 and BD2); ET, extra-terminal domain; PWWP, Proline-Tryptophan-Tryptophan-Proline domain; PHD, plant homeo-domain-type zinc-finger motifs; SET, Su(var)3-9, Enhancer-of-zeste and Trithorax (SET) domain; C/H rich, SET-associated Cys-His-rich (SAC) domain].

Figure 3

Feed-forward model of megadomain formation. (A) BRD4-NUTM1 is tethered to acetylated chromatin by BRD4 bromodomains. EP300 is recruited by the NUTM1 portion of the fusion, leading to increased local histone acetylation and, subsequently, (B) a self-perpetuating recruitment of BRD4-NUTM1 complexes. The resultant uncontrolled spreading of BRD4-NUTM1 within the chromatin leads to the formation of megadomains that are typically limited only by topologically associating domain boundaries (not shown). The Mediator subunit 24 (MED) interacts physically with BRD4 as a target and a cofactor of BRD4-NUTM1, to provide another positive reinforcement loop for the establishment of megadomains and their transcriptional activity.