Abstract
Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants. The only characteristic, recurrent genetic aberration of AT/RTs is biallelic inactivation of SMARCB1 (or SMARCA4). These genes are members of the mSWI/SNF chromatin-remodeling complex, which regulates various developmental processes, including neural differentiation. This review explores AT/RT subgroups regarding their distinct SMARCB1 loss-of-function mechanisms, molecular features, and patient characteristics. Additionally, it addresses the ongoing debate about the oncogenic relevance of cell-of-origin, examining the influence of developmental stage and lineage commitment of the seeding cell on tumor malignancy and other characteristics. Epigenetic dysregulation, particularly through the regulation of histone modifications and DNA hypermethylation, has been shown to play an integral role in AT/RTs' malignancy and differentiation blockage, maintaining cells in a poorly differentiated state via the insufficient activation of differentiation-related genes. Here, the differentiation blockage and its contribution to malignancy are also explored in a cellular context. Understanding these mechanisms and AT/RT heterogeneity is crucial for therapeutic improvements against AT/RTs.