Robustness and cross-cohort concordance of developmental regulons in endometrial carcinoma

Abstract

Claims about regulatory differences among endometrial carcinoma molecular classes must distinguish association, target-set robustness, and cross-cohort transportability. We evaluated a fetal Müllerian epithelial module and 20 prespecified developmental transcription-factor regulons in 507 TCGA-UCEC tumours and assessed six signals in 230 CPTAC-UCEC tumours. The global fetal module was non-confirmatory. GATA2 and SOX9 showed negative POLE-plus-MMRd versus NSMP effects in TCGA and the same direction in both CPTAC strata, but neither passed the universal single-target-deletion gate. HOXA9 and WT1 lacked external confirmation, while PAX8 and LHX1 were internally robust but externally unresolved. The evidence supports cross-cohort directional concordance for selected regulons while keeping pointwise association, target-set robustness, and transportability as separate claims. It does not establish biomarker validity, causal transcription-factor activity, therapeutic dependence, treatment response, or clinical utility. The computational and reproducibility record corresponding to this preprint is archived as GitHub release v1.0.1 at https://doi.org/10.5281/zenodo.21762178.