Abstract
BACKGROUND: Gene expression-based molecular subtypes in glioblastoma from The Cancer Genome Atlas Network (TCGA-GBM) unraveled the pathological origins by identifying tumour cell driver genes. However, the causal inference between molecular subtype origins and their therapeutic efficacy remains obscure. METHODS: We integrated TCGA-GBM multi-omics (DNA, mRNA, and protein profiles) using correlation analysis to identify cis-regulation. We analyzed the exposure-mediated base substitution-level mutations and their potential triggers. Importantly, we performed Consensus Clustering based on the MSigDB database with Silhouette-correction to identify prognostically relevant pathway-based MSig subtypes. The tumour driver mutations (co-occurrence mutation pattern), aberrant pathways (tumour hallmarks), immune microenvironment (xCell), and pseudo-time analysis (dyno) were used to characterize the MSig subtype landscape. Furthermore, we evaluated potential drug sensitivities across MSig subtypes using the Genomics of Drug Sensitivity in Cancer database. RESULTS: We classified five MSig subtypes, characterized by neural-like, tumour-driving, low tumour evolution, immune-inflamed, and classical tumour features. We observed several key features in 'tumour-driving' GBM patients: (1) mutual exclusivity between prognostic factors TP53 and EGFR; and (2) IDH1 mutations co-occurring with TP53, which account for the protective role of IDH1 in TP53 mutant patients. The immune-inflamed GBM, characterized as a 'hot' tumour, exhibited upregulation of immune-related pathways, including PD-1 and IFN-γ signalling responses. DNA methylation landscape revealed 14 MGMT CpG-rich regions regulating expression. Evolutionary trajectories revealed progression from a primary tumour state (close to normal tissue) to two distinct endpoints (tumour-driving and immune-inflamed subtypes). CONCLUSIONS: Our findings reveal interactions between tumour cells and their surrounding immune environment, classifying GBM into two newly identified subtypes: (1) the tumour-driving subtype is characterized by multiple oncogenic mutations, while (2) the immune-blockade subtype is marked by a high presence of immune cells. We highlight the importance of integrating multi-type data (somatic mutations, DNA methylation, and RNA transcripts, etc.) to decipher GBM biology and potential therapeutic implications. HIGHLIGHTS: We report the interaction between tumor cells and environmental immune cells, classifying GBM into two main subtypes: 1) The tumor-driving subtype is characterized by multiple oncogenic mutations, while 2) the immune-blockage subtype is marked by a high presence of immune cells. We used integrated multidimensional analyses of somatic mutations, DNA methylation, and RNA transcripts to gain a deeper understanding of GBM biology and potential therapeutic implications.