Genomic and mutational landscape of anaplastic ependymoma: Insights from the AACR Project GENIE Consortium

Anaplastic ependymoma (AE) is a rare and aggressive central nervous system tumor that predominantly affects children and remains inadequately characterized at the genomic level. This study aimed to delineate the genomic and demographic landscape of histologically defined AE while identifying potential therapeutic targets. We conducted a retrospective analysis of AE cases from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) repository via cBioPortal, examining recurrent somatic mutations, copy number alterations, mutation co-occurrence, and exploratory sex- and race-based enrichment using descriptive and non-parametric statistics. The most frequent alterations included mutations in the telomerase reverse transcriptase (TERT) promoter, followed by recurrent changes in lysine methyltransferase 2D (KMT2D), lysine methyltransferase 2A (KMT2A), lysine methyltransferase 2C (KMT2C), E1A binding protein p300 (EP300), additional sex combs like 1 (ASXL1), and SET domain containing 2 (SETD2), indicating significant disruption of chromatin remodeling. Recurrent alterations in tumor protein p53 (TP53), ataxia telangiectasia mutated (ATM), and cyclin-dependent kinase inhibitor 2A (CDKN2A) suggested dysregulation of the p53 and DNA damage response pathways. Additionally, alterations in notch receptor 1 (NOTCH1) and notch receptor 2 (NOTCH2) indicated aberrant NOTCH signaling. Neurofibromin 2 (NF2) mutations were observed in male patients, and exploratory subgroup differences emerged across racial groups. Overall, AE appears to be driven by recurrent alterations in chromatin remodeling, p53, DNA damage response, and NOTCH signaling pathways, highlighting these areas as priorities for future biological validation and therapeutic investigation.