ATRX loss in sarcomas is associated with dysregulated gene and transposable element expression, loss of DNA methylation, and worse survival

Background ATRX is a tumor suppressor and key regulator of transcriptionally repressive epigenetic states. We investigate the impact of ATRX loss on gene expression, DNA methylation, and transposable element (TE) expression in common soft tissue sarcoma tumors, a family of rare cancers.

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.

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 (plog-rank=0.0023).

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. Competing Interest Statement BAN receives collaborative in kind research support from Epicypher and STORM therapeutics, research funding (to institution) from Servier, and advisory/consulting fees from Parabilis Medicines. All other authors declare no conflicts of interest. Funding Statement We gratefully acknowledge the support of the Burroughs Wellcome Fund/Physician Scientist Incubator Program and the T32 Award (5T32HD071834) for Research Training for Pediatric Subspecialty Fellows through the Department of Pediatrics at UPMC Children s Hospital of Pittsburgh. B.A.N. is a Damon Runyon Clinical Investigator supported in part by the Damon Runyon Cancer Foundation (CI-124-23) as well as NCI K08 CA245212. The Hillman Cancer Center Support Grant (P30 CA047904) partly supported this work through shared resource centers. This project used the UPMC Hillman Cancer Center (HCC) Cancer Biostatistics Facility. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study only used data that is available from the TCGA database and published manuscripts as cited. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The study only used data that is available from the TCGA database and published manuscripts as cited.