NUTM1-Rearranged Neoplasms—A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations—An Updated Review

Abstract

Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update on NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.

Optical Genome Mapping Identifies a Novel Pediatric Embryonal Tumor Subtype with a ZNF532-NUTM1 Fusion

“…NUTM1- rearranged tumors have a chromosomal translocation resulting in the fusion of the NUTM1 gene on chromosome 15 with a gene involved in transcription regulation. The most common fusion partner is BRD4 (chromosome 19) but fusions involving BRD3 (chromosome 9), NSD3 (chromosome 8) and zinc finger genes ( ZNF ) such as the ZNF532 (chromosome 18) seen in our patient have also been described[20]. NUTM1 rearrangements are most commonly associated with sarcomas and hematologic malignancies in both children and adults, although a variety of other cancers have also been identified.…”

“…NUTM1 , is the NUT midline carcinoma gene family member 1 and located on chromosome 15q14[20]. NUTM1- rearranged tumors have a chromosomal translocation resulting in the fusion of the NUTM1 gene on chromosome 15 with a gene involved in transcription regulation.…”

“…NUTM1 rearrangements are most commonly associated with sarcomas and hematologic malignancies in both children and adults, although a variety of other cancers have also been identified. Children and infants with NUTM1 fusions in B-cell ALL have favorable prognosis, while the clinical impact of this fusion on sarcomas is still unclear[20,21].…”

“…Radiation therapy has also been shown to have some benefit in patients with NUTM1- rearranged midline tumors and has primarily been used in older patients with localized disease[26]. Chemotherapy has had mixed responses and thus far has not been demonstrated to improve overall outcomes in patients with these tumors[20,27]. However, a standardized therapeutic approach has not yet been identified in children or adults with NUT- rearranged tumors, so additional studies would be required to fully understand the role of surgery, radiation therapy, and chemotherapy in patients with these tumors.…”

The generation of a Nutm1 knock-in reporter mouse line for imaging post-meiotic spermatogenesis

“…Although Nutm1 specifically expresses and functions in the male germline under physiological conditions, it is also a recurrent fusion partner for a large group of poorly understood cancers named Nutm1- rearranged neoplasms 15 . Our Nutm1-T2A-Luc2TdTomato reporter line may contribute to future research into these cancers and have broader applications outside reproductive biology.…”