Cross‐Cancer Profiling of CDH1 Reveals Context‐Dependent EMT Decoupling, Immune Heterogeneity, and Prognostic Variability in Epithelial Cancers

ABSTRACT

Cadherin 1 ( CDH1 ) encodes E‐cadherin, a key epithelial adhesion molecule traditionally associated with tumor suppression and epithelial–mesenchymal transition (EMT). However, its roles across cancers remain incompletely understood, particularly within multilayer regulatory contexts involving genomic, epigenetic, transcriptional, and immune mechanisms. CDH1 expression, survival associations, EMT‐correlated gene profiles ( VIM , SNAI1 , and ZEB1 ), immune infiltration patterns, immune checkpoint correlations ( PDCD1 , CD274 , and CTLA4 ), promoter methylation, and genomic alterations were assessed across five epithelial cancers, breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), lung adenocarcinoma (LUAD), ovarian serous cystadenocarcinoma (OV), and stomach adenocarcinoma (STAD). Cross‐platform analysis was performed using The Cancer Genome Atlas (TCGA)/Genomic Data Commons (GDC) datasets, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, TIMER, KM Plotter, cBioPortal, and g:Profiler. CDH1 was overexpressed but showed variable prognostic significance; TCGA/GDC analyses were nonsignificant, whereas KM Plotter showed better survival in COAD, LUAD, and STAD, worse survival in BRCA, and no association in OV. Classic inverse relationships between CDH1 and VIM or ZEB1 were evident only in STAD, and SNAI1 showed no consistent association. Immune infiltration patterns were tumor‐specific, ranging from cytotoxic T‐cell dominance in LUAD to macrophage‐rich profiles in OV; immune checkpoint correlations were similarly context‐dependent. Cancer‐specific enrichment revealed distinct trafficking‐ and adhesion‐related profiles. Promoter methylation patterns varied by cancer, whereas genomic alterations of CDH1 were rare. CDH1 does not function as a universal epithelial or EMT marker across epithelial cancers. Instead, its associations with EMT, immune contexture, methylation, and prognosis are context‐dependent, supporting a model of CDH1 as a heterogeneous regulator of epithelial plasticity. These findings challenge single‐function interpretations and support cancer‐specific CDH1 evaluation in translational research.