A systematic scoping review of the molecular pathogenesis of digestive system cancers (2013-2025).

Digestive system cancers (DSCs) remain among the most prevalent and lethal malignancies worldwide, accounting for more than a quarter of cancer diagnoses and a third of cancer deaths. Advances in next-generation sequencing (NGS) have accelerated discovery of genetic, epigenetic, and transcriptomic alterations, yet an integrated overview across DSCs is lacking. This scoping review synthesized 57 studies published between 2013 and 2025 from PubMed, Scopus, and Web of Science. Colorectal and gastric cancers were most frequently represented, while oesophageal, pancreatic, and rare subtypes such as gallbladder and ampullary cancers were under-studied. Recurrent alterations in TP53, KRAS, PIK3CA, and CDKN2A were identified, alongside mismatch repair deficiency and microsatellite instability in colorectal and gastric cancers. Emerging evidence from recently published studies further highlights the contribution of germline alterations and increased molecular heterogeneity in selected DSC subtypes. Epigenetic dysregulation and recent applications of single-cell and spatial transcriptomics highlighted tumour heterogeneity. Despite progress, evidence remains uneven across cancer types, with limited exploration of germline variants beyond colorectal, pancreatic, and select liver cancers.