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

Background 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. Methods 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. Results 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