Alsugair Ziyad, Karanian Marie, Meurgey Alexandra, Treilleux Isabelle, Renard Caroline, Phelinas Simon, Glehen Olivier, Kepenekian Vahan, Meeus Pierre, Thamphya Brice, Pissaloux Daniel, Tirode Franck, Benzerdjeb Nazim
Department of Pathology, Institut de Pathologie Multisite, Hospices Civils de Lyon, CHU Lyon Sud, Pierre-Bénite, France; Biopathology department, Centre Leon Berard, Lyon, France.
Biopathology department, Centre Leon Berard, Lyon, France; Team Genetics, Epigenetics and Biology of Sarcomas, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France.
Mod Pathol. 2025 Jun 13;38(10):100816. doi: 10.1016/j.modpat.2025.100816.
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.
新出现的证据表明，NUTM1重排也发生在非癌性肿瘤中，包括皮肤肿瘤、白血病和高级别肉瘤。最近，在腹腔内发现了一个独特的NUTM1重排肉瘤亚群，主要起源于结肠，基于有限的甲基化分析，其分子特征有所不同。本研究旨在从临床、组织学、免疫组织化学和转录组学水平进一步探索5例NUTM1/NUTM2重排的腹腔内肉瘤患者。纳入的患者均为无癌症病史的女性；她们的平均年龄为51.6岁（范围：29 - 73岁）。肿瘤位于腹腔内，包括乙状结肠、膀胱子宫韧带和升结肠黏膜下层。3例患者尽管接受了化疗，但仍出现疾病进展，在诊断后1至8个月内死亡。观察到多种组织学模式，包括上皮样增生、紧密和疏松区域、横纹肌样细胞和梭形细胞束。免疫组织化学方面，大多数标志物为阴性；所有病例雌激素受体均为阳性，而NUT仅在NUTM1重排的病例中呈阳性。在3例病例中鉴定出MXD4::NUTM1融合，在其他病例中，鉴定出NUTM2B与MXD4或MXI1的融合。均匀流形近似和投影聚类分析表明，NUTM1/NUTM2B重排的腹腔内肉瘤聚集在一起，与其他肿瘤不同。层次聚类树状图显示，NUTM1/NUTM2B腹腔内重排肉瘤与NUTM1重排癌、NUTM1重排皮脂腺癌、MGA::NUTM1肉瘤和NUTM1重排子宫内膜间质肉瘤有更大的分离。ESR1在NUTM1/NUTM2B重排的腹腔内肉瘤中的表达明显更高。本文中的NUTM1/2B重排腹腔内肉瘤代表了一种在转录组水平上与肉瘤谱系不同的新实体，其特征是雌激素受体过表达，这可能是另一种治疗选择的指征。
