Abstract
Central nervous system low-grade diffusely infiltrative tumor with INI1 deficiency (CNS LGDIT-INI1) is a pathologically low-grade tumor characterized by the infiltrative growth of INI1-deficient tumor cells. Although CNS LGDIT-INI1 is known to progress to an atypical teratoid/rhabdoid (AT/RT)-like tumor, little is yet known about the molecular characteristics distinguishing CNS LGDIT-INI1 from AT/RT. To elucidate the molecular profile of CNS LGDIT-INI1, we performed whole-genome sequencing (WGS), RNA-seq, and DNA methylation array analysis on three cases (1 child and 2 adults) with CNS LGDIT-INI1, including a paired primary-recurrent case. Additionally, 44 publicly available AT/RT cases were analyzed. All the three cases demonstrate homozygous deletions of the SMARCB1 gene, supporting its fundamental role in the tumorigenesis of CNS LGDIT-INI1. The median number of somatic mutations is 1.3/Mb (1.0-2.8) predominantly comprising age-related C-to-T transitions at the CpG site, which is slightly higher than 0.82/Mb in AT/RT, potentially suggesting an association with advanced age of onset. CNS LGDIT-INI1 exhibits a relatively stable genome where broad copy number variations are extremely rare except for the SMARCB1 region, whereas the AT/RT genome shows multiple copy number alterations. Gene set enrichment analysis based on gene expression reveals that CNS LGDIT-INI1 exhibits relatively lower activation in the cell cycle and protein translational activity compared to AT/RT, which is consistent with the low cell proliferation in CNS LGDIT-INI1. The DNA methylation profile of LGDIT resembles that of AT/RT-MYC, suggesting a common cell of origin between CNS LGDIT-INI1 and AT/RT-MYC. In conclusion, CNS LGDIT-INI1 grows based on the loss of SMARCB1, exhibiting a stable genome and low proliferation activity. Considering the similarity of the DNA methylation profile and SMARCB1 deficiency, it is suggested that CNS LGDIT-INI1 may be a precursor of AT/RT.