Radiomic Features of MRI Subcompartments Associate with Angiogenic and Inflammatory Transcriptomic Programs in...

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 MGMT 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 (R²_cv ≤ 0). Inflammatory Response (R²_cv = 0.185, 95% CI [0.071, 0.355], p = 0.008) was the only pathway supported by both the nested CV (FDR = 0.096) and the exploratory LMM (FDR = 0.024, ΔR² = 0.214 beyond subcompartment effects) analyses; the LMM association was robust to clinical covariate adjustment (likelihood ratio test p = 0.004). Angiogenesis (R²_cv = 0.209, 95% CI [0.028, 0.353], p = 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.