Brunetti Marta, Vitelli Valeria, Naas Anca Mihaela, Zahl Eriksson Ane Gerda, Haugland Hans Kristian, Krakstad Camilla, Micci Francesca
Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Oslo, Norway.
JCO Precis Oncol. 2025 May;9:e2400779. doi: 10.1200/PO-24-00779. Epub 2025 May 22.
The molecular heterogeneity of endometrial stromal tumors (ESTs) is demonstrated by the presence of the same fusion gene in distinct pathologic entities, such as endometrial nodules and low-grade endometrial stromal sarcoma, both exhibiting the chimeric transcript. Given the limited knowledge on these tumors, which is based on a small number of cases studied with a restricted range of techniques, we analyzed 47 ESTs to explore their methylation and transcriptomic landscapes.
Tumor methylation and transcriptomes profiles were investigated.
The methylation profile showed distinct clusters, which correlated with established histopathologic and molecular subtypes. The highest methylation value was reported for nuclear factor of activated T cytoplasmic 1, and the lowest was detected for miR34C. Two different 5'-C-phosphate-G-3' (CpG) sites of ( and ), along with , showed the same methylation pattern in both low-grade and high-grade endometrial stromal sarcoma (HG-ESS). Similarly, , , , , and showed identical methylation patterns in HG-ESS and undifferentiated uterine sarcomas, highlighting the similarities between these tumors within the EST spectrum. We identified 13 novel fusion transcripts involving several genes that are active in transcriptional regulation.
In ESTs, the genes involved in chromosomal rearrangements function as transcription regulators, either directly through the formation of zinc finger motifs or indirectly through epigenetic regulation. The methylation signature is different for distinct subgroups of the EST spectrum, with more aggressive tumors, HG-ESS, and undifferentiated uterine sarcoma, clustering together. Some genes showed similar methylation levels in different entities, highlighting the presence of a continuum in the tumor profile. Methylation levels of CpG sites at specific gene loci may serve as valuable biomarkers for these tumors.
子宫内膜间质肿瘤（ESTs）的分子异质性表现为在不同的病理实体中存在相同的融合基因，如子宫内膜结节和低级别子宫内膜间质肉瘤，二者均表现出嵌合转录本。鉴于对这些肿瘤的了解有限，且基于少量病例并采用有限的技术进行研究，我们分析了47例ESTs以探索其甲基化和转录组图谱。
研究肿瘤甲基化和转录组图谱。
甲基化图谱显示出不同的聚类，与既定的组织病理学和分子亚型相关。活化T细胞质1核因子的甲基化值最高，而miR34C的甲基化值最低。（和）的两个不同的5'-C-磷酸-G-3'（CpG）位点以及，在低级别和高级别子宫内膜间质肉瘤（HG-ESS）中显示出相同的甲基化模式。同样，，，，和在HG-ESS和未分化子宫肉瘤中显示出相同的甲基化模式，突出了EST谱系内这些肿瘤之间的相似性。我们鉴定出13种涉及多个参与转录调控基因的新型融合转录本。
在ESTs中，参与染色体重排的基因作为转录调节因子发挥作用，要么直接通过锌指基序的形成，要么间接通过表观遗传调控。EST谱系不同亚组的甲基化特征不同，侵袭性更强的肿瘤、HG-ESS和未分化子宫肉瘤聚集在一起。一些基因在不同实体中显示出相似的甲基化水平，突出了肿瘤特征中存在连续性。特定基因位点的CpG位点甲基化水平可能作为这些肿瘤有价值的生物标志物。
