Study · Endometrial regulons

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

Prespecified TCGA-UCEC discovery with CPTAC-UCEC external evaluation, target-deletion robustness and clinical sensitivity analyses.

Authors

Draga Toncheva1Vasil Sgurev2Vladimir Mitev3

  1. 1Department of Biological Sciences, Bulgarian Academy of Sciences
  2. 2Institute of Information and Communication Technologies, Bulgarian Academy of Sciences
  3. 3Helena Bioinformatics EOOD

Abstract

This study asks whether the molecular classes of endometrial carcinoma differ in developmental regulatory programmes while keeping association, target-set robustness and cross-cohort transportability as separate claims.

A fetal Müllerian epithelial module and 20 prespecified developmental transcription-factor regulons were evaluated in TCGA-UCEC. Six signals then underwent external evaluation in two independent CPTAC-UCEC strata, together with deletion, purity, molecular-subtype, grade and histology sensitivity analyses.

Read the preprintView on GitHub

Two regulons hold their prespecified direction in an independent cohort. None is presented as a validated biomarker.

01 · Effect estimates

Cross-cohort forest plot

−1.5−1.0−0.50.0+0.5+1.0+1.5GATA2C2GATA2: d −0.553, 95% CI −0.855 to −0.287, q 0.0020−0.553SOX9C2SOX9: d −0.527, 95% CI −0.805 to −0.287, q 0.0020−0.527HOXA9C2HOXA9: d −0.646, 95% CI −0.921 to −0.382, q 0.0020−0.646WT1C2WT1: d −0.591, 95% CI −0.878 to −0.349, q 0.0020−0.591PAX8C1PAX8: d +0.693, 95% CI +0.473 to +0.924, q 0.0020+0.693LHX1C1LHX1: d +0.962, 95% CI +0.734 to +1.207, q 0.0020+0.962standardized effect size d
ZeroLocked |d| = 0.50 floorValues and intervals: GitHub scientific release
This site presents cohort-level research results. It does not provide patient-specific interpretation, treatment prediction or clinical decision support.
Releasev1.0.1
DiscoveryTCGA-UCEC · n=507
External evaluationCPTAC-UCEC · n=230
Scientific commitf702249bd50d

Analysis workflow

A frozen, reproducible sequence from cohort definition to external evaluation.

Analysis workflow · Step 01

Prespecification

Twenty developmental transcription-factor regulons and the broad fetal Müllerian M1 module were frozen before external evaluation.

Purpose

Define the analysis before the independent cohort was evaluated.

Method

The M1 module, 20 regulons, target definitions and planned contrasts were fixed in the study release.

Output

A fixed analysis inventory that the discovery, robustness and external-evaluation steps use without changing the original scope.

Analysis workflow · Step 02

Discovery

Cohort-level standardized effects were estimated in TCGA-UCEC primary tumours.

Purpose

Estimate molecular-class contrasts in the primary cohort.

Method

Standardized effect sizes, confidence intervals and multiplicity-adjusted results were calculated for the prespecified TCGA-UCEC analysis.

Output

Primary estimates for the six canonical targets, retained as association evidence rather than clinical effects.

Analysis workflow · Step 03

Robustness

Purity removal and leave-one-target-out analyses tested sensitivity to modelling choices and regulon membership.

Purpose

Test whether a result depends on tumour-purity adjustment or one target gene.

Method

The completed no-purity model and target-deletion runs were compared with the primary specification.

Output

Sensitivity and deletion-robustness records that remain separate from external confirmation.

Analysis workflow · Step 04

External evaluation

CPTAC-UCEC strata were combined with a fixed-effect meta-analysis; direction, uncertainty and multiplicity were retained.

Purpose

Evaluate the prespecified direction in an independent cohort.

Method

Discovery and Confirmatory CPTAC-UCEC strata were estimated separately and then combined with a fixed-effect model.

Output

External estimates, intervals and direction-based credit or veto status for each canonical target.

Analysis workflow · Step 05

Claim boundary

Association, robustness and transportability are reported separately; no causal or clinical claim is made.

Purpose

Keep the interpretation within the evidence produced by the study.

Method

Association, robustness, external direction and uncertainty remain separate dimensions without a composite score.

Output

Cohort-level research findings that are not presented as causal activity, biomarker validation or clinical decision support.