Unveiling divergent treatment prognoses in IDHwt-GBM subtypes through multiomics clustering: a swift dual MRI-mRNA model for precise subtype prediction
Authors: Ji Qiang , Zheng Yi , Zhou Lili , Chen Feng , Li Wenbin 
Published: June 2024

Abstract
Background
IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in accurately predicting patient outcomes. To address these issues and personalise treatment approaches, we aimed to develop and validate robust multiomics molecular subtypes of IDHwt-GBM. Through this, we sought to uncover the distinct molecular signatures underlying these subtypes, paving the way for improved diagnosis and targeted therapy for this challenging disease.

Methods
To identify stable molecular subtypes among 184 IDHwt-GBM patients from TCGA, we used the consensus clustering method to consolidate the results from ten advanced multiomics clustering approaches based on mRNA, lncRNA, and mutation data. We developed subtype prediction models using the PAM and machine learning algorithms based on mRNA and MRI data for enhanced clinical utility. These models were validated in five independent datasets, and an online interactive system was created. We conducted a comprehensive assessment of the clinical impact, drug treatment response, and molecular associations of the IDHwt-GBM subtypes.

Results
In the TCGA cohort, two molecular subtypes, class 1 and class 2, were identified through multiomics clustering of IDHwt-GBM patients. There was a significant difference in survival between Class 1 and Class 2 patients, with a hazard ratio (HR) of 1.68 [1.15–2.47]. This difference was validated in other datasets (CGGA: HR = 1.75[1.04, 2.94]; CPTAC: HR = 1.79[1.09–2.91]; GALSS: HR = 1.66[1.09–2.54]; UCSF: HR = 1.33[1.00–1.77]; UPENN HR = 1.29[1.04–1.58]). Additionally, class 2 was more sensitive to treatment with radiotherapy combined with temozolomide, and this sensitivity was validated in the GLASS cohort. Correspondingly, class 2 and class 1 exhibited significant differences in mutation patterns, enriched pathways, programmed cell death (PCD), and the tumour immune microenvironment. Class 2 had more mutation signatures associated with defective DNA mismatch repair (P = 0.0021). Enriched pathways of differentially expressed genes in class 1 and class 2 (P-adjust < 0.05) were mainly related to ferroptosis, the PD-1 checkpoint pathway, the JAK-STAT signalling pathway, and other programmed cell death and immune-related pathways. The different cell death modes and immune microenvironments were validated across multiple datasets. Finally, our developed survival prediction model, which integrates molecular subtypes, age, and sex, demonstrated clinical benefits based on the decision curve in the test set. We deployed the molecular subtyping prediction model and survival prediction model online, allowing interactive use and facilitating user convenience.

Conclusions
Molecular subtypes were identified and verified through multiomics clustering in IDHwt-GBM patients. These subtypes are linked to specific mutation patterns, the immune microenvironment, prognoses, and treatment responses.