ArticlemedRxiv : the preprint server for health sciences2025
ATRX loss in sarcomas is associated with dysregulated gene and transposable element expression, loss of DNA methylation, and worse survival.
Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Methods: Using data from The Cancer Genome Atlas (TCGA), we analyzed 234 tumors from patients with dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS), soft tissue leiomyosarcoma (LMS), uterine LMS (uLMS), and myxofibrosarcoma (MFS). Corresponding clinical outcome and patient data, DNA sequencing, RNA sequencing, and 450K methylation data were integrated to assess ATRX-dependent features. Results: ATRX loss was associated with significantly altered gene expression with the greatest impact in LMS/uLMS with 31 (33.0%) genes downregulated and 63 (66.0%) genes upregulated (FDR < 0.05), consistent with a role for ATRX in transcriptional silencing. Methylation profiling identified 269 differentially methylated CpGs (FDR<0.05), with a marked hypomethylation effect. ATRX loss was associated with loss of TE silencing with 97% (n=93) of differentially expressed TEs upregulated, indicating that ATRX loss contributes to a marked de-repression of TEs. The median overall survival in LMS patients was 81.0 vs 34.9 months for tumors with ATRX retention and loss (p Conclusions: ATRX loss in sarcomas leads to DNA hypomethylation, increased expression of TEs, as well as transcriptional dysregulation affecting key oncogenic pathways. ATRX status may serve as a potential biomarker for prognosis and therapeutic stratification. Future clinical trials investigating epigenetic therapies could offer novel treatment strategies for ATRX-deficient sarcomas.
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