Gastric cancer (GC) is responsible for approximately 763,000 annual deaths worldwide, ranking fifth in mortality rates and sixth in terms of cancer types with the highest incidence. The most common type of GC is intestinal-type gastric cancer. In most cases, this cancer develops from a series of well-defined pathological states, starting with non-atrophic gastritis (NAG) that can progress towards precancerous lesions (PL), including atrophic gastritis (AG), intestinal metaplasia (IM), dysplasia, and finally, GC. In Colombia, GC is the leading cause of cancer-related deaths, and in the Andean region in southwestern Colombia, the incidence and mortality rates of GC are among the highest in the country. In this region, a cohort of patients has been followed since 1991.

We examined 63 gastric tissue samples from patients who were followed up for 16 years. Biopsies from three stages - NAG, IM, and dysplasia - were collected and analyzed using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Additionally, three samples of normal gastric tissue were included for analysis.

We have identified and reported quantitative data for 8351 proteins that were confidently quantified. This revealed dysregulated pathways and processes at different stages. Differentially expressed proteins (DEPs) increased as the lesions progressed. The most significant dysregulation was found in proteins in the dysplasia stage compared to the IM and NAG stages. We also found four protein clusters with similar trajectories, indicating dynamic and progressive changes in proteomic profiles from non-atrophic to advanced gastric lesions.

Three clusters showed a decrease in expression as they progressed to PL. The protein AP1B1 exhibited a clear tendency to decrease its expression, significantly reducing dysplasia. Another protein cluster showed increased expression in NAG, which remained stable until MI but markedly increased expression in dysplasia. Proteins SFN, GOLM1, ABRACL, ANKLE2, STMN1, MYL12A, S100A10, TAGLN2, and EXO1 tended to increase from normal tissue to NAG, then to IM, with a significant increase observed in dysplasia. IM was characterized by the downregulation of proteins related to nonsense-mediated decay (NMD) and the Unfolded Protein Response, with overexpression of proteins associated with the immune system.

The transformation to dysplasia involves overexpression of oxidative phosphorylation, apoptosis, oxidative stress, and the downregulation of proteins involved in DNA repair, telomere maintenance, chromatin remodeling, regulation of cell-cell adhesion, and different signaling pathways in carcinogenesis. Differentially expressed proteins (DEPs) in dysplasia, namely STMN1, SRI, CLIC1, and SPARC1, which have a prior association with GC, show a gradual increase from NAG to GLP. Together, these findings suggest that changes in the expression of specific proteins are associated with the progression of gastric lesions towards malignancy.