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NUTM1/NUTM2B-Rearranged Intra-abdominal Sarcomas: A Distinct Entity From Sarcomas With ESR1 Overexpression as a
Ziyad Alsugair1, Marie Karanian2, Alexandra Meurgey3
1Department of Pathology, Institut de Pathologie Multisite, Hospices Civils de Lyon, CHU Lyon Sud, Pierre-Bénite, France; Biopathology department, Centre Leon Berard, Lyon, France.
Abstract:
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.
Insights
NUTM1/NUTM2-rearranged intra-abdominal sarcomas are a distinct emerging cancer entity. These sarcomas show high estrogen receptor expression, suggesting potential new therapeutic avenues for this rare cancer.
Area of Science:
- Oncology
- Molecular Pathology
- Genomics
Background:
- NUTM1 rearrangements are increasingly identified in various non-carcinoma tumors, including sarcomas.
- A specific subset of intra-abdominal sarcomas with NUTM1 rearrangements has been recently identified, showing distinct molecular features.
Purpose of the Study:
- To comprehensively investigate NUTM1/NUTM2-rearranged intra-abdominal sarcomas using clinical, histologic, immunohistochemical, and transcriptomic analyses.
- To characterize the molecular and clinical features of this rare sarcoma subtype and differentiate it from other neoplasms.
Main Methods:
- Clinical and histological data collection from 5 patients with NUTM1/NUTM2-rearranged intra-abdominal sarcomas.
- Immunohistochemical staining for various markers, including NUT.
- Transcriptomic analysis to identify gene fusions (e.g., MXD4::NUTM1, NUTM2B fusions) and gene expression patterns (e.g., ESR1).
- Uniform Manifold Approximation and Projection (UMAP) clustering for transcriptomic data analysis.
Main Results:
- NUTM1/NUTM2-rearranged intra-abdominal sarcomas present in middle-aged females with diverse intra-abdominal locations and varied histologic patterns.
- Transcriptomic analysis revealed MXD4::NUTM1 fusions in 3 cases and NUTM2B fusions in others, clustering these sarcomas separately from other neoplasms.
- Significantly higher ESR1 (estrogen receptor 1) expression was observed in these sarcomas compared to other NUTM1-rearranged tumors.
Conclusions:
- NUTM1/NUTM2-rearranged intra-abdominal sarcomas represent a distinct molecular and transcriptomic entity.
- The observed overexpression of estrogen receptors highlights a potential therapeutic target for this emerging sarcoma subtype.
