Explainable Deep Radiogenomic Molecular Imaging for MGMT Methylation Prediction in Glioblastoma

Abstract

Glioblastoma (GBM) is a highly aggressive primary brain tumor with limited therapeutic options and poor prognosis. The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is a critical molecular biomarker that influences patient response to temozolomide chemotherapy. Traditional methods for determining MGMT status rely on invasive biopsies and are limited by intratumoral heterogeneity and procedural risks. This study presents a radiogenomic molecular imaging analysis framework for the non-invasive prediction of MGMT promoter methylation using multi-parametric magnetic resonance imaging (mpMRI). Our approach integrates radiomics, deep learning, and explainable artificial intelligence (XAI) to analyze MRI-derived imaging phenotypes and correlate them with molecular labels. Radiomic features are extracted from FLAIR, T1-weighted, T1-contrast-enhanced, and T2-weighted MRI sequences, while a 3D convolutional neural network learns deep representations from the same modalities. These complementary features are fused using both early fusion and attention-based strategies and classified to predict MGMT methylation status. To enhance clinical interpretability, we apply XAI methods such as Grad-CAM and SHAP to visualize and explain model decisions. The proposed framework is trained on the RSNA-MICCAI Radiogenomic Classification dataset and externally validated on the BraTS 2021 dataset. This work advances the field of molecular imaging by demonstrating the potential of AI-driven radiogenomics for precision oncology, supporting non-invasive, accurate, and interpretable prediction of clinically actionable molecular biomarkers in GBM.