Year: 2026
Type: article
Abstract: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma characterized by the pathognomonic EWS::WT1 fusion protein (FP), an oncogenic chimeric transcription factor (OCTF) resulting from the t(11;22)(p13;q12) translocation. Recent studies have identified "neogenes" (NGs), genes normally silent in normal tissues but transcriptionally activated by OCTFs, as potential tumor-specific markers in fusion-driven cancers. In this study, we investigated the expression and regulation of DSRCT-specific NGs (DSRCT_NGs) using multimodal data across different cohorts of patients, PDX, and cell line data. We evaluated bulk and single-nucleus RNA sequencing of patient specimens from MD Anderson Cancer Center, revealing the robust ability for DSRCT_NGs to distinguish FP-positive DSRCT from samples failing detection of the EWS::WT1 FP. To elucidate the regulatory role of the EWS::WT1 FP in driving NG expression, we performed knockdown experiments in four DSRCT cell lines. This consistently resulted in a reduction of DSRCT_NG expression. Isoform-specific expression of EWS::WT1 in LP9 and MeT-5A mesothelial cells revealed that the E-KTS isoform of EWS::WT1 predominantly drives DSRCT_NG expression. Mechanistically, ATAC-seq and ChIP-seq analyses demonstrated that EWS::WT1 directly binds to accessible chromatin regions near NG transcription start sites, enriched for WT1 motifs and active histone marks. Integration of Hi-ChIP data further revealed that EWS::WT1 facilitates long-range enhancer-promoter looping at DSRCT_NG loci, promoting the expression of nearby genes. Collectively, these findings establish DSRCT_NGs as direct transcriptional outputs of the EWS::WT1 FP and implicate their loci as regulatory regions of the DSRCT transcriptome. Their fusion-dependent expression, chromatin accessibility, and promoter-enhancer connectivity underscore their potential utility as highly specific biomarkers and therapeutic targets in DSRCT.
Source: Communications Biology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,190
Funders: U.S. Department of Defense, Rally Foundation, Sarcoma Foundation of America, Cancer Prevention and Research Institute of Texas, Sarcoma Alliance for Research through Collaboration, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Institute of General Medical Sciences
Awards: An Integrative Approach to Identify Vulnerabilities in Pediatric Cancer DSRCT, NEUROENDOCRINE REPROGRAMMING IN DSRCT RESISTANCE MECHANISMS AND TREATMENT STRATEGIES, G293715275, G387944721, G4276892241, Single Cell Spatial Analysis in Tissue, Medical Scientist Training Program, Pediatric Solid Tumors Comprehensive Data Resource Core, NovaSeq6000, The epigenetic impact and therapeutic opportunity of AR directed therapy for DSRCT, G7761418987, G8696838854, Cancer Center Support Grant
OpenAlex ID: W7215058794