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.

Keywords: NUT protein; NUTM1 gene; neoplasms; pathogenesis; therapy.

Figure 1

(A–D). Histology of NUTM1-rearranged neoplasms. (A) NUT carcinoma showing undifferentiated morphology with abrupt keratinization. (B) Small blue cell sarcoma with MGA-NUTM1 fusion composed of monomorphic small blue cells forming rosettes. (C) Porocarcinoma with YAP1-NUTM1 fusion showing features reminiscent of abrupt keratinization as seen in NUT carcinoma but having lumens and a cuticle, typical for poroid differentiation, and much more bland cytology than NUT carcinoma. (D) NUT immunostain in the porocarcinoma (Clone C52B1, Cell Signaling) showing diffuse and strong nuclear expression.

Figure 2

HDAC expression in NUT carcinoma. Thirty-two NUT and 22 lung carcinoma cases from biopsied patients and assayed by NGS at Caris Life Sciences between 2019 and 2021. Whole transcriptome sequencing RNA-seq (WTS) provided a measure of expression in TPM (transcripts per million molecules, as generated by Salmon). WTS used the Agilent Whole Exome SureSelect V7 bait set for RNA capture.