NUTM1/NUTM2B-Rearranged Intra-abdominal Sarcomas: A Distinct Entity From Sarcomas With ESR1 Overexpression as a Therapeutic Target.

Emerging evidence reports that NUTM1 rearrangements also occur in noncarcinomas, including skin tumors, leukemias, and high-grade sarcomas. Recently, a distinct subset of NUTM1-rearranged sarcomas was identified intra-abdominally, mainly of colonic origin, differing molecularly, based on limited methylation analysis. This study aimed to further explore 5 patients with NUTM1/NUTM2-rearranged intra-abdominal sarcomas at clinical, histologic, immunohistochemical, and transcriptomic levels. The included patients were all females without a history of cancer; their mean age was 51.6 years (range: 29-73). Tumors were located intra-abdominally, including the sigmoid colon, the vesicouterine ligament, and the submucosa of the ascending colon. Three patients experienced disease progression despite chemotherapy, resulting in death within 1 to 8 months from diagnosis. Diverse histologic patterns were observed, including epithelioid proliferation, cohesive and dyscohesive areas, rhabdoid cells, and spindle cell fascicles. Immunohistochemically, most markers were negative; all cases were positive for estrogen receptors, whereas NUT was positive only in NUMT1-rearranged cases. MXD4::NUTM1 fusions were identified in 3 cases, and in the other cases, NUTM2B fusions were identified with either MXD4 or MXI1. Uniform manifold approximation and projection clustering analysis demonstrated that NUTM1/NUMT2B-rearranged intra-abdominal sarcomas clustered together, apart from other neoplasms. The hierarchical clustering dendrogram displayed a greater separation of NUTM1/NUMT2B intra-abdominal-rearranged sarcomas from NUTM1-rearranged carcinomas and NUTM1-rearranged porocarcinomas, from MGA::NUTM1 sarcomas and NUTM1-rearranged endometrial stromal sarcomas. ESR1 expression was significantly higher in NUTM1/NUMT2B-rearranged intra-abdominal sarcomas. NUTM1/2B-rearranged intra-abdominal sarcomas herein represent an emerging entity distinct from the sarcomatous lineage at the transcriptomic level and characterized by its overexpression of estrogen receptors, which could be an indication for another therapeutic option.