Development and Validation of a PRS for Gastric Cancer Risk Stratification in Europe

Abstract Gastric cancer (GC) is the 5th most common cancer and the 4th leading cause of cancer-related deaths worldwide, with poor prognosis and regional disparities driven by lifestyle and genetic factors. While Polygenic Risk Scores (PRS) have advanced risk prediction in other cancers, limited research has addressed GC, particularly in European populations. This study develops and validates a PRS for GC risk, aiming to improve early detection and personalized prevention. Moreover, we assess the change in discriminatory accuracy of the addition of PRS into prediction models with only traditional risk factors. Our study includes about 8,247 GC cases and 353,694 controls with GWAS data, along with demographic, lifestyles and clinical data. Of these, around 6,350 cases and 14,963 controls from Helsinki Biobank, Rotterdam Study, the StoP Consortium (Italy, Spain, Poland, Sweden, France, Portugal), and additional cohorts from Germany and Estonia are used in the development phase; and around 1,900 cases and 339,231 controls from independent cohorts of the StoP Consortium (Rome, Latvia, Lithuania) and the UK Biobank in the validation phase. GC-associated SNPs are identified and combined via inverse-variance-weighted meta-analysis. Finally, the PRS is integrated with traditional risk factors into a risk prediction model to evaluate its effectiveness. Preliminary findings show differing distributions of established risk factors between GC cases and controls, with higher alcohol (11.2% vs. 8.8%) and smoking (29.1% vs. 25.2%) prevalences in GC. Moreover, SNPs linked to GC risk are mapped to chromosomes 1, 2, 4, 8, 9, and 17. A meta-analysis across cohorts is underway to refine these associations and constructing a PRS for GC. A validated PRS for GC can enable personalized risk stratification by integrating the cumulative impact of multiple genetic variants, thereby identifying individuals at elevated genetic risk who may benefit from targeted surveillance and preventive strategies. Key messages • Aggregating the effects of multiple SNPs, PRS can refine GC risk stratification by categorizing individuals into different risk groups and allowing for more personalized screening strategies. • The PRS constructed and validated from large European cohorts can improve GC risk stratification, potentially allowing for more targeted surveillance and preventive measures.