Quantitative and qualitative assessment of metaplasia and oncogenesis in gastrointestinal tract cancers reveal pseudogenes as regulators

Chronic inflammation drives aberrant epithelial differentiation and often leads to metaplasia, a common precursor to gastrointestinal tract cancers (GITCANs). While multiple coding genes in GITCANs are well-characterized, the role of non-coding RNAs, particularly pseudogenes, remains unclear. Here, we present a comprehensive pan-GITCAN analysis of metaplastic epithelia using a suite of computational tools: POpCan, QuantPlasia, and PlasiaCorrelationProfiler. Spatiotemporal expression specificity of differentiation-associated pseudogenes was characterized by POpCan, while QuantPlasia estimated tissue-resident and metaplasia-associated differentiation, thereby revealing a unique stage for each GITCAN. Stratification of these unique stages based on pseudogene expression showed that combinatorial deregulation of differentiation-associated pseudogenes correlated with metaplasia-associated differentiation. Notably, PlasiaCorrelationProfiler further demonstrated that metaplastic epithelia, despite their histological resemblance to the normal tissues of adjacent gastrointestinal organs, shared genotypic features with corresponding cancers. This alignment was especially pronounced in stratified cohorts, where genotypic correlation was observed between the cohorts exhibiting combinatorial deregulation of pseudogenes and cancers of adjacent gastrointestinal organs. Combinatorial deregulation of pseudogenes was also associated with transcriptional bursting, increased mutational burden, and copy number alterations. Finally, survival analysis and coding potential evaluation identified pseudogenes with putative protein-coding capacity as potential biomarkers of GITCAN progression, highlighting their significance in early detection and therapeutic targeting.