Pathway-level somatic mutation burden reflects diffuse genomic accumulation rather than selective transcriptional...

Whether increasing tumor mutation burden (TMB) drives selective transcriptional pathway disruption or reflects diffuse genomic accumulation in ovarian serous carcinoma remains unclear.

TMB-transcriptome relationships were examined in the CPTAC-GDC cohort (n = 84) using Spearman correlations between continuous TMB and ssGSEA-derived Hallmark pathway scores. Pathway-level somatic mutations were aggregated into TCGA categories. External validation used the Gray Foundation GeoMx spatial transcriptomics cohort (n = 43) and MSK SPECTRUM multi-region genomic cohort (n = 42).

No detectable TMB-pathway activity associations were identified after FDR correction (all FDR > 0.30; all |ρ| < 0.25), robust to hypermutator exclusion and TP53-mutant subgroup analysis (n = 66; all FDR > 0.66). Chromatin remodeling was the only pathway with significant TMB-correlated mutation accumulation (ρ = +0.481, FDR < 0.001), persisting after gene-length normalization. TP53 pathway mutation density showed an expected arithmetic decrease in high-TMB tumors (median 0.247 vs. 0.667, p = 0.0002). Spatial profiling confirmed compartment-dependent pathway activity, with chromatin remodeling enriched in epithelial compartments (Δ = +0.375, FDR < 0.001). MSK SPECTRUM confirmed the TP53 density pattern (ρ = -0.991) and universal TP53 mutation (100% vs. 79.8% in discovery).

No detectable association between TMB and transcriptional pathway activity was observed in ovarian serous carcinoma under the statistical power of this study. Chromatin remodeling is preferentially mutated with increasing TMB and compartment-enriched in epithelial cells. These findings underscore the importance of spatially resolved, histologically validated analyses for interpreting pathway biology in HGSC.