Current advances in the management of atypical teratoid rhabdoid tumors (ATRT)

Atypical teratoid rhabdoid tumors (ATRT) are rare, often lethal embryonal tumors of the central nervous system (CNS) that primarily affect very young children. Intensive multimodal approaches have resulted in improvements in survival albeit with significant associated toxicity. Recent molecular studies have led to the discovery of SMARCB1 inactivation and resultant BAF47/INI1 loss as the near-universal key genetic event that leads to widespread epigenetic dysregulation. Rarely, SMARCA4 encoding BRG1 is impacted. SMARCB1 and SMARCA4 are core subunits of the SWI/SNF chromatin remodeling complex, which is a fundamental epigenetic regulator of gene transcription. Up to a third of patients diagnosed with ATRT have Rhabdoid Tumor Predisposition Syndrome (RTPS) characterized by germline SMARCB1 (or SMARCA4) alterations. Patients with RTPS are at increased risk of developing synchronous or metachronous rhabdoid tumors outside the CNS. At least three molecular subgroups of ATRT (ATRT-TYR, ATRT-SHH, ATRT-MYC) have been identified through large-scale DNA methylation and transcriptomic studies, with each subgroup having distinct transcriptional, epigenomic and clinicopathologic features. In this book chapter, we will summarize key epidemiological and clinical features of ATRT, review current conventional multimodal regimens, summarize key findings from conducted prospective trials and recently concluded (2020 to present) meta-analyses, as well as discuss emerging targeted treatment approaches that exploit potential therapeutic vulnerabilities of this epigenetically influenced tumor.