PATH-23. SARCOMATOUS TRANSFORMATION OF GLIOBLASTOMA IS ASSOCIATED WITH A DISTINCT MOLECULAR SIGNATURE

Abstract A subset of IDH-wildtype glioblastoma (GBM) undergo sarcomatous transformation to gliosarcoma at recurrence which is associated with a propensity for dural and calvarial invasion. However, the underlying biology of sarcomatous transformation and predictive biomarkers for these aggressive tumors are unknown. We performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Eighteen patients (17%) developed sarcomatous transformation at recurrence as defined by fascicular growth, intercellular reticulin deposition, and immunohistochemical evidence of glial to mesenchymal transdifferentiation. Compared to conventional GBM, patients who developed gliosarcoma had shorter interval between initial surgery and first recurrence (8.3 vs. 11.2 months, p=0.002) and reduced overall survival (18.2 vs. 21.9 months, p=0.164). While there were no differences in sex, age, tumor location, or adjuvant therapy, we found differences in the molecular signatures of GBM that transformed to gliosarcoma at recurrence, including a significant enrichment in NF1, TP53, and RB1 alterations and an absence of EGFR amplification. GBM which underwent sarcomatous transformation were enriched for the Mesenchymal epigenetic class at initial surgery (69% vs. 25%) and became enriched for the novel Mesenchymal subclass B at recurrence (43% vs. 2%). Among approximately 850,000 interrogated CpG sites, we identified 1,503 and 2,090 CpG sites within gene regulatory regions that were significantly more hypermethylated or hypomethylated in those initial GBM that transformed to gliosarcoma at recurrence compared to those that did not. Gene Ontology biologic processes enriched in these differentially methylated genes include immune cell signaling, cell-cell adhesion, and TGF-beta signaling. Together, these findings reveal GBM which undergo transformation to gliosarcoma represent a biologically distinct subtype with aggressive clinical course. Enrichment for NF1 and RB1 alterations and differentially methylated immune cell and TGF-beta signaling suggests potential unique therapeutic vulnerabilities for affected patients.