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

ATRX (α-thalassemia/mental retardation syndrome X-linked) is a tumor suppressor and key regulator of transcriptionally repressive epigenetic states. We investigate the impact of somatic ATRX loss of function 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, undifferentiated pleomorphic sarcoma, soft tissue leiomyosarcoma (LMS), uterine LMS, and myxofibrosarcoma. 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/uterine LMS with reduction of expression of 31 (33%) genes and 63 (67%) genes up-regulated (false discovery rate <0.05), consistent with a role for ATRX in transcriptional silencing. Methylation profiling identified 269 differentially methylated CpGs (false discovery rate <0.05), with a marked hypomethylation effect (88% of CpGs) across all sarcomas. ATRX loss was associated with loss of TE silencing with 97% (n = 93) of differentially expressed TEs up-regulated, indicating that ATRX loss contributes to a marked de-repression of TEs. The median overall survival in LMS patients was 81.0 versus 34.9 months for tumors with ATRX retention and loss (p_log-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 mutational 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.