Abstract
Leiomyosarcomas (LMS) are diverse, rare, and aggressive mesenchymal soft tissue sarcomas. Epigenetic alterations influence multiple aspects of cancer, however epigenetic profiling of LMS has been limited. The goal of this study was to delineate the molecular landscape of LMS for subtype-specific differences (uterine LMS (ULMS) vs soft tissue LMS (STLMS)) based on integrated analysis of DNA methylation and gene expression to identify potential targets for therapeutic intervention and diagnosis. We identified differentially methylated and differentially expressed genes associated with ULMS and STLMS using DNA methylation and RNA-seq data from primary tumors. Two main clusters were identified through unsupervised hierarchical clustering: ULMS-enriched cluster and STLMS-enriched cluster. The integrated analysis demonstrated 34 genes associated with hypermethylation of the promoter CpG islands and downregulation of gene expression in ULMS or STLMS. In summary, these results indicate that differential DNA methylation and gene expression patterns are associated with ULMS and STLMS. Further studies are needed to delineate the contribution of epigenetic regulation to LMS subtype-specific gene expression and determine the roles of the differentially methylated and differentially expressed genes as potential therapeutic targets or biomarkers.
Highlights
Leiomyosarcomas (LMS) are aggressive heterogeneous mesenchymal neoplasms that account for 10–20% of soft tissue sarcomas [1]
Heatmap representation of an unsupervised hierarchical clustering analysis (HCA) based on the differentially methylated CpG regions (DMRs) demonstrated that the majority of the LMS samples segregate into two main clusters based on the subtype status: uterine LMS (ULMS)-enriched cluster and soft tissue LMS (STLMS)-enriched cluster (Figure 2B)
Heatmap representation of an unsupervised HCA based on the 3,263 DMRs hypermethylated in ULMS demonstrated the distinct separation of ULMS and STLMS samples (Supplementary Figure 1)
Summary
Leiomyosarcomas (LMS) are aggressive heterogeneous mesenchymal neoplasms that account for 10–20% of soft tissue sarcomas [1]. Diagnosed patients are at high risk of distant recurrence and poor disease-specific survival [2]. The 5-year survival rate is 42% for all stages and only 14% with distant spread, based on data from the Surveillance, Epidemiology, and End Results Program (SEER) datasets. The approval of tazemetostat for patients with metastatic epithelioid sarcomas has been the first time an epigenetic modifier was shown to have a role in the treatment of soft tissue sarcomas [10]. There is little data regarding factors that influence survival in LMS patients underscoring the need for studies to understand the genetic and epigenetic factors involved in LMS which influence treatment response
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