New molecular signatures map the stepwise development of gastric cancer

Gastric cancer often develops through a gradual sequence of changes, beginning with superficial gastritis and advancing through chronic atrophic gastritis, intestinal metaplasia, and precancerous lesions before culminating in malignancy. Helicobacter pylori infection, responsible for nearly 90% of non-cardia gastric cancers, plays a central role in triggering this cascade. While eradication therapy reduces risk, the molecular events that connect infection to cancer progression remain poorly understood. Previous studies have focused on individual pathways such as inflammation or immune response but lacked an integrated perspective. Due to these challenges, a deeper investigation into the molecular signatures of H. pylori-related carcinogenesis is needed to guide prevention and risk prediction.

A research team from Peking University Cancer Hospital & Institute and collaborating institutions published (DOI: 10.20892/j.issn.2095-3941.2025.0077) their findings on September 2025 in Cancer Biology & Medicine. The study applied large-scale proteomic profiling and single-cell transcriptomic sequencing to human gastric tissues spanning multiple stages of disease. By integrating prospective follow-up data and population-level plasma proteomics, the researchers uncovered robust protein signatures linking H. pylori infection to gastric lesion progression and cancer risk. Their work provides both mechanistic insight and potential biomarkers for early identification of individuals most vulnerable to developing gastric cancer.

The investigation analyzed gastric tissue samples from 166 individuals in Linqu, a high-risk region in China, and 99 patients in Beijing, profiling over 4,200 proteins. From this dataset, 28 proteins were validated as key markers of H. pylori infection and gastric cancer, including up-regulated proteins such as OLFM4 and ENO1 and down-regulated proteins like GSN and IGFBP2. Single-cell RNA sequencing of 135,000 gastric cells revealed that these protein-encoding genes exhibited stage-specific expression shifts during the transition from normal epithelium to intestinal metaplasia and ultimately malignant cells. To test predictive utility, the team built a 15-protein tissue panel that stratified patients by cancer risk: those in the highest quartile had over seven-fold increased odds of progressing to neoplasia. Extending these findings, a four-protein circulating panel (OLFM4, ENO1, GSN, IGFBP2) was validated in the UK Biobank cohort of 48,529 participants. Individuals in the high-risk group were nearly four times more likely to develop gastric cancer compared to those in the lowest risk group. Together, these results highlight a reproducible molecular trajectory that may underlie infection-driven gastric carcinogenesis.

By integrating tissue proteomics, single-cell sequencing, and long-term follow-up data, we have been able to identify consistent protein markers that map the stepwise development of gastric cancer. These findings not only improve our understanding of how H. pylori infection reshapes the gastric environment but also provide powerful tools for risk stratification. Such biomarkers could be instrumental in designing targeted surveillance and early prevention programs for populations at high risk of gastric cancer."

Dr. Wenqing Li, senior author of the study

The establishment of tissue-based and circulating protein panels holds promise for transforming gastric cancer prevention strategies. Currently, endoscopic screening is costly and invasive, limiting widespread implementation, particularly in resource-constrained regions. Non-invasive blood-based markers could enable scalable, population-level screening to identify individuals who most urgently require follow-up. Beyond clinical applications, the molecular signatures identified in this study shed light on the fundamental biology of infection-induced cancer, offering potential drug targets for therapeutic intervention. As these biomarkers are further validated, they could form the basis of precision medicine approaches that intercept gastric cancer development at its earliest stages.