Abstract 6248: Multilayered molecular interactions underlying glioblastoma pathogenesis through multi-omics analysis

Abstract Glioblastoma, IDH-wild type (GBM) is the most common malignant and treatment-refractory brain tumor with a dismal prognosis. Despite the identification of various driver genes in previous large-scale genomic analyses, there has been limited progress in the development of novel treatments. Acquiring an extensive understanding of the molecular mechanisms underlying GBM pathogenesis is crucial to improve prognostic outcomes. We analyzed 289 whole-genome sequencing data (WGS) including 159 unpublished deep WGS (≥ ×120 coverage) along with RNA-seq, DNA methylation array, and assay for transposase-accessible chromatin with sequencing (ATAC-seq) to uncover the molecular mechanisms regulating development and progression of GBM. Our deep WGS enables us to delineate a fine view of clonal architecture, where mutational signature varies between clonal and subclonal mutations, suggesting that different mutational processes contribute to GBM pathogenesis depending on its developmental stage. The differentiation status of tumor cells detected by transcriptional deconvolution analysis is associated with multi-layer profiles including genomic alterations, expression subtypes, DNA methylation, and open chromatin status. Tumors predominantly comprised of differentiated cells display genetic and epigenetic profiles that align with the classical subtype, whereas tumors predominantly composed of stem-like cells exhibit profiles consistent with the proneural subtype. ATAC-seq unveils genome-wide chromatin accessibility features associated with gene expression subtypes. Motif enrichment analysis of differentially accessible sites among the subtypes identified specific transcription factors. The proneural subtype is enriched for the SOX10 binding motif, which is associated with regulating cell states, and exhibits higher expression of SOX10 compared to other subtypes. Conversely, the mesenchymal and classical subtypes are enriched for the CREB1 binding motif, which promotes cell proliferation and angiogenesis through TGFβ2 upregulation, wherein TGFβ2 expression is significantly elevated. These findings support a model in which the difference in chromatin structure also regulates the progression of GBM. Our analysis reveals the multi-layer molecular interactions underlying the progression of GBM enhancing our understanding of the pathogenesis. Citation Format: Takuma Nakashima, Yusuke Funakoshi, Ryo Yamamoto, Yuriko Sugihara, Shohei Nambu, Yoshiki Arakawa, Shota Tanaka, Joji Ishida, Ryuta Saito, Ryosuke Hanaya, Koji Yoshimoto, Yoshitaka Narita, Hiromichi Suzuki. Multilayered molecular interactions underlying glioblastoma pathogenesis through multi-omics analysis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6248.