Low-Grade Myofibroblastic Sarcoma Represents an Epigenetically Distinct Myofibroblastic Tumor With USP6 Upregulation...

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• Low-grade myofibroblastic sarcoma (LGMS) is a rare mesenchymal neoplasm with unclear molecular underpinnings and relationships to similar tumors.
• Previous studies have lacked comprehensive multiomics data, hindering a full understanding of LGMS pathogenesis.

Purpose of the Study:

• To conduct the first comprehensive multiomics analysis of LGMS.
• To define the molecular basis, genomic stability, and epigenetic distinctiveness of LGMS.
• To compare LGMS with related fibroblastic tumors and identify potential therapeutic targets.

Main Methods:

• Whole-exome sequencing (WES), RNA sequencing, and Illumina MethylationEPIC v2 array profiling were performed on six LGMS cases.
• Comparative analysis was conducted against public sarcoma methylation cohorts and related fibroblastic tumors.
• Clinical and follow-up data were analyzed for patient outcomes.

Main Results:

• LGMS cases exhibited low tumor mutational burden and genomic stability, with specific gene deletions (TP53, TSC2) and amplifications (NTRK1, ERBB3) in a subset.
• Distinct transcriptomic signature characterized by USP6 overexpression and upregulation of inflammatory/immune genes (e.g., CD274/PD-L1).
• Epigenetic analysis revealed LGMS forms a unique methylation cluster, closest to inflammatory myofibroblastic tumor, with increased immune infiltration.

Conclusions:

• LGMS is a genomically stable, epigenetically distinct entity driven by USP6 overexpression and an inflammation-enriched transcriptome.
• Findings support LGMS recognition as a standalone tumor type and its integration into methylation-based diagnostic classifiers.
• USP6 pathways and immune checkpoint blockade are promising therapeutic strategies for LGMS.