Stepwise accumulation of chromosomal copy number variations along the gastritis-carcinoma sequence: implications for early risk stratification in gastric cancer

Background Gastric cancer poses a serious threat to public health, and the current screening is of limited efficiency. Chromosomal copy number variation (CNV) is a major driver of gastric carcinogenesis, yet its stepwise evolution along the gastritis–carcinoma sequence remains poorly delineated. Dissecting the dynamic landscape of CNVs may yield crucial biomarkers for early risk stratification.Methods In this study, we performed cost-effective low-coverage whole-genome sequencing (LC-WGS) on 101 gastric mucosal specimens encompassing non-atrophic gastritis (NAG, n = 15), atrophic gastritis (AG, n = 35), high-grade intraepithelial neoplasia or early gastric cancer (HGIN/EGC, n = 33), and advanced gastric cancer (AGC, n = 18).Results The frequency of CNV at both the complete chromosome and chromosomal-arm level showed a stepwise increase along the gastritis–carcinoma sequence. Two novel quantitative indices, MaxZ and CountZ, were developed to respectively measure the magnitude and extent of chromosomal imbalance, both of which correlated strongly with histologic progression (ρ > 0.4, p < 0.001). Recurrent alterations included gains on chromosomes 20, 8q and 7p and losses on chromosomes 4, which accumulated along the sequence and may represent key CNV events underlying malignant transformation. Notably, clustering analysis identified a high-CNV subgroup within AG (n = 5) exhibiting CNV profiles resembling gastric cancer.Conclusions These preliminary CNV signatures suggest potential value for identifying high-risk individuals in precancerous lesions, particularly within AG, and offer an exploratory molecular basis that may inform future early screening and diagnosis of gastric cancer.