Radiomic Features of MRI Subcompartments Associate with Angiogenic and Inflammatory Transcriptomic Programs in Glioblastoma: An IvyGAP Exploratory Analysis.

Glioblastoma exhibits profound intratumoral heterogeneity, with anatomically distinct tumor zones characterized by divergent molecular programs that drive therapy resistance. Whether magnetic resonance imaging (MRI)-derived radiomic features can capture these regional transcriptomic differences remains unknown. We aimed to determine whether subcompartment-level radiomic features associate with transcriptomic pathway enrichment scores derived from biologically approximate tumor zones. We matched 28 patients (mean age 58.5 years; 13/28 methylated) across the IvyGAP RNA-seq atlas and the IVYGAP-RADIOMICS datasets. Single-sample GSEA (ssGSEA) pathway scores were computed for 24 gene sets. Radiomic features (3920 per subcompartment) were reduced to 597. Nested leave-one-patient-out cross-validation (LOPO-CV) with Elastic Net served as the primary predictive analysis; linear mixed-effects models (LMM) provided exploratory associational analysis. Analyses used a biologically motivated but spatially non-co-registered zone-to-subcompartment mapping; all reported associations are zone-approximate. Twenty-one of 24 pathways showed no predictive signal (R ≤ 0). Inflammatory Response (R = 0.185, 95% CI [0.071, 0.355], = 0.008) was the only pathway supported by both the nested CV (FDR = 0.096) and the exploratory LMM (FDR = 0.024, ΔR = 0.214 beyond subcompartment effects) analyses; the LMM association was robust to clinical covariate adjustment (likelihood ratio test = 0.004). Angiogenesis (R = 0.209, 95% CI [0.028, 0.353], = 0.006) reached nested CV significance (FDR = 0.096) but was not corroborated by the LMM (FDR = 0.445); it is therefore reported as a tentative single-framework signal requiring independent validation. T2-derived texture features were selected in 100% of folds for both pathways. Inflammatory Response is the only pathway supported by both analytical frameworks; Angiogenesis is a tentative nested-CV-only signal pending independent validation. The absence of signal for 21 of 24 pathways should not be interpreted as evidence of biological inaccessibility: at N = 28 (vs. N ≈ 240 required by Riley criteria), severe underpowering, attenuation from the non-spatial zone-to-subcompartment mapping, and methodological constraints each independently suffice to suppress real associations. Five of the 24 gene sets (the IvyGAP zone modules) are non-independent from the outcome data and cannot be interpreted as discovery. All reported associations are zone-approximate and may partly reflect macro-compartment (between-subcompartment) effects; validation in larger cohorts with spatially precise co-registration is essential.