NUTM1 Gene Fusions Characterize a Subset of Undifferentiated Soft Tissue and Visceral Tumors

Abstract

NUT midline carcinoma is an aggressive tumor that occurs mainly in the head and neck and, less frequently, the mediastinum and lung. Following identification of an index case of a NUTM1 fusion positive undifferentiated soft tissue tumor, we interrogated additional cases of primary undifferentiated soft tissue and visceral tumors for NUTM1 abnormalities. Targeted next-generation sequencing was performed on RNA extracted from formalin-fixed paraffin-embedded tissue, and results validated by fluorescence in situ hybridization using custom bacterial artificial chromosome probes. Six patients were identified: mean age of 42 years (range, 3 to 71 y); equal sex distribution; and, tumors involved the extremity soft tissues (N=2), kidney (N=2), stomach, and brain. On systemic work-up at presentation all patients lacked a distant primary tumor. Morphologically, the tumors were heterogenous, with undifferentiated round-epithelioid-rhabdoid cells arranged in solid sheets, nests, and cords. Mitotic activity was generally brisk. Four cases expressed pancytokeratin, but in only 2 cases was this diffuse. Next-generation sequencing demonstrated the following fusions: BRD4-NUTM1 (3 cases), BRD3-NUTM1, MXD1-NUTM1, and BCORL1-NUTM1. Independent testing by fluorescence in situ hybridization confirmed the presence of NUTM1 and partner gene rearrangement. This study establishes that NUT-associated tumors transgress the midline and account for a subset of primitive neoplasms occurring in soft tissue and viscera. Tumors harboring NUTM1 gene fusions are presumably underrecognized, and the extent to which they account for undifferentiated mesenchymal, neuroendocrine, and/or epithelial neoplasms is unclear. Moreover, the relationship, if any, between NUT-associated tumors in soft tissue and/or viscera, and conventional NUT carcinoma, remains to be elucidated.

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

“…Most recently, six cases of soft tissue and visceral neoplasms harboring NUTM1 fusion genes have been reported. These tumors occurring outside the anatomic midline were diagnosed with undifferentiated tumors based on histological and immunohistochemical findings, and these tumors are suggested to be “ NUT ‐associated tumors.”44 Our case harboring the NUTM1 fusion gene would also be classified as a “ NUT ‐associated tumor,” and undifferentiated mesenchymal, neuroendocrine, and epithelial tumors should be reassessed by immunohistochemical and fusion gene analyses because “ NUT ‐associated tumors” may be underdiagnosed 44…”

“…Approximately two‐thirds of NMC cases harbor a BRD4–NUTM1 fusion gene, which has been functionally validated as an oncogenic event 39, 40. In the other one‐third of cases, several fusion partners of NUTM1 have been reported in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman) and recent papers, such as ACIN1, 41, 42, 43 BCOR1, 44 BRD3, 40 BRD9, 41 BPTF, 45 CIC, 46 CUX1, 42 IKZF1, 42, 47 MXD1, 44 NSD3, 48 SLC12A6, 42 ZNF532, 49 and ZNF618. 42 Although MXD1–NUTM1 fusion has been reported in gastric sarcoma, MXD4 has not been previously reported as a fusion partner of NUTM1.…”

Primary malignant epithelioid and rhabdoid tumor of bone harboring ZNF532‐NUTM1 fusion: the expanding NUT cancer family

“…5 Unlike typical NC, squamous differentiation is not a feature in these tumors, and the expressions of cytokeratin and p63 are inconsistent. 5 Unlike typical NC, squamous differentiation is not a feature in these tumors, and the expressions of cytokeratin and p63 are inconsistent.…”

“…5 Unlike typical NC, squamous differentiation is not a feature in these tumors, and the expressions of cytokeratin and p63 are inconsistent. 5,8 BRD4 (bromodomain containing 4) is the most common fusion partner gene in NC, accounting for about 70% of cases. 5,8 BRD4 (bromodomain containing 4) is the most common fusion partner gene in NC, accounting for about 70% of cases.…”

“…2 With high sensitivity (87%) and specificity (100%), NUT immunostain has been utilized as a diagnostic substitute for molecular testing. [5][6][7][8][9][10][11][12][13] These tumors exhibit a wider and more heterogeneous morphologic spectrum compared to typical NC. 4 Recently, NUTM1 gene rearrangements have been increasingly identified in other cancers.…”