Transcriptomic profiling reveals conserved stage‐associated programs across gastrointestinal adenocarcinomas

Abstract Background Gastrointestinal (GI) adenocarcinomas exhibit substantial molecular heterogeneity despite their shared epithelial origin and anatomical continuity. Whether these anatomically distinct cancers share conserved transcriptomic programs associated with pathological stage remains unclear. Aims This study aimed to identify conserved transcriptomic programs associated with pathological stage across pan‐GI adenocarcinomas using an integrated transcriptomic network analysis approach. Methods and results RNA sequencing data from oesophageal, gastric, colon and rectal adenocarcinomas in The Cancer Genome Atlas were integrated into a stage‐stratified pan‐GI cohort. Weighted gene co‐expression network analysis identified conserved co‐expression modules, which were validated through hub gene validation in independent Clinical Proteomic Tumor Analysis Consortium Phase cohorts and module preservation analysis in Gene Expression Omnibus datasets. Functional enrichment, differential expression, miRNA–mRNA regulatory network and survival analyses were subsequently performed. Two conserved co‐expression modules remained significantly associated with pathological stage after adjustment for age, sex and primary anatomical site. These modules were enriched for intracellular signalling and extracellular matrix‐related pathways and contained seven consistently dysregulated validated hub genes ( ZEB1 , FERMT2 , MPDZ , LRCH2 , ZFPM2 , GLI3 and PDGFRB ), together with three candidate regulatory microRNAs ( hsa‐miR‐19a , hsa‐miR‐19b and hsa‐miR‐20a ). Conclusion Pan‐GI transcriptomic profiling identified conserved epithelial‐ and stromal‐associated molecular programs shared across anatomically distinct GI adenocarcinomas. These reproducible transcriptomic features provide a systems‐level framework for understanding shared disease biology and establish a foundation for future mechanistic studies and stage‐informed therapeutic strategies.