Genetic heterogeneity and key driver mutations in the preneoplastic and earliest stages of gastric cancer.

Background: Gastric cancer (GC) is the fifth-leading cause of cancer-related mortality, with a 5-year survival rate less than 20%. It develops from preneoplastic lesions to adenocarcinoma, but these early genetic alterations remain poorly understood. Therefore, we aimed to identify early genetic drivers underlying the development of preneoplastic lesions and the initiation of gastric carcinogenesis. Methods: We characterized preneoplastic and early gastric adenocarcinoma using 48 samples from 16 Guatemalan patients, a country with a high incidence of GC. We sequenced a panel of 127 genes to identify early genetic drivers and possible actionable targets. Results: We identified extensive genetic heterogeneity, including single nucleotide and copy number variations. After comparing our data with other studies, we identified TP53 and APC as the most mutated genes in preneoplastic lesions and early GC. Our mean tumor mutational burden was higher in diffuse (0.017 mutations/Mb) and intestinal adenocarcinomas (0.015) than in chronic gastritis (0.005), and analysis of the mutational signatures revealed several processes acting at different stages of the disease. Signatures S15 (DNA mismatch repair deficiency) and S03 (homologous recombination deficiency) were more frequent in early adenocarcinoma than in chronic gastritis, intestinal metaplasia, necrosis, tubular adenoma, and atrophy. Notably, 10 of 16 patients (62.5%) had at least one actionable mutation in their preneoplastic lesions or gastric adenocarcinomas. Conclusions: We show that at the preneoplastic and earliest stages, GC is genetically heterogeneous and presents key cancer-driving mutations that may participate in neoplastic transformation and progression, with 62.5% of lesions having the potential for treatment. This study expands the limited research on early GC and highlights key opportunities for precision medicine in populations with high GC incidence.