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The remarkable heterogeneity of glioblastoma, across patients and over time, is one of the main challenges in precision diagnostics and treatment planning. Non-invasive  in vivo  characterization of this heterogeneity using imaging could assist in understanding disease subtypes, as well as in risk-stratification and treatment planning of glioblastoma. The current study leveraged advanced imaging analytics and radiomic approaches applied to multi-parametric MRI of  de novo  glioblastoma patients ( n  = 208 discovery,  n  = 53 replication), and discovered three distinct and reproducible imaging subtypes of glioblastoma, with differential clinical outcome and underlying molecular characteristics, including isocitrate dehydrogenase-1 ( IDH1 ), O 6 -methylguanine–DNA methyltransferase, epidermal growth factor receptor variant III ( EGFRvIII ), and transcriptomic subtype composition. The subtypes provided risk-stratification substantially beyond that provided by WHO classifications. Within  IDH1 -wildtype tumors, our subtypes revealed different survival ( p  < 0.001), thereby highlighting the synergistic consideration of molecular and imaging measures for prognostication. Moreover, the imaging characteristics suggest that subtype-specific treatment of peritumoral infiltrated brain tissue might be more effective than current uniform standard-of-care. Finally, our analysis found subtype-specific radiogenomic signatures of  EGFRvIII -mutated tumors. The identified subtypes and their clinical and molecular correlates provide an  in vivo  portrait of phenotypic heterogeneity in glioblastoma, which points to the need for precision diagnostics and personalized treatment.

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Radiomic MRI signature reveals three distinct subtypes of glioblastoma with different clinical and molecular characteristics, offering prognostic value beyond IDH1