10206-GGE-21 MOLECULAR LANDSCAPE AND TUMOR EVOLUTION IN ASTROBLASTOMA

Abstract

Abstract Astroblastoma is an extremely rare malignant brain tumor characterized by distinctive gene fusions, including MN1-BEND2 and EWSR1-BEND2 fusions. Despite its indolent nature, frequent local recurrence affects the quality of life for patients. However, there remains a lack of investigation into the genome of astroblastoma. To elucidate the molecular landscape and clonal evolution of astroblastoma, we conducted deep whole-genome sequencing, RNA-seq, and DNA methylation array on 11 cases, including multi-time point samples from 3 cases. Additionally, we integrated publicly available RNA-seq and/or DNA methylation array data from 9 cases. The cohort consists of 13 cases with MN1-BEND2 fusion and 7 cases with EWSR1-BEND2 fusion. Astroblastoma exhibits a relatively silent genome, with median mutation rate is 0.60/Mb (0.22 - 1.09), which is associated with patient age. While EWSR1-BEND2 fusions result from simple translocation, MN1-BEND2 fusions predominantly arise from complex chromosomal rearrangements between chromosome X and 22, frequently involving an additional chromosome, leading to massive oscillation of copy number states in the affected chromosome. Breakpoints in BEND2 within EWSR1-BEND2 fused cases are located near the N-terminus while breakpoints in BEND2 within MN1-BEND2 fused cases cluster in the middle of the gene, suggesting that functional region in BEND2 fusion is distinct based on its partner. Based on DNA methylation, astroblastoma can be divided into three subgroups: MN1-child, MN1-adult, and EWSR1-BEND2 fusion. Gene set enrichment analysis reveals the activation of mitochondrial metabolism in EWSR1-BEND2 fused cases. MN1-adult cases exhibit activation of oxidative stress and DNA replication, whereas MN1-child cases show activation of NOTCH signaling. Multi-time point analysis demonstrates the architecture of clonal evolution. Ionizing radiation appears to be associated with an increase in mutations and deletions, with a radiation-related signature. Our comprehensive analysis provides a detailed view of the genome and evolutionary trajectory of astroblastoma.