Genome wide association analysis and association of genetic risk and lifestyle with upper gastrointestinal cancer among an endoscopy-screened cohort in China.

Esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC) are influenced by genetic and lifestyle factors. We quantified genetic, lifestyle, and joint effects on upper gastrointestinal (UGI) cancer and evaluated the clinical utility of polygenic risk scores (PRS) for risk stratification. We included 5556 participants from a prospective endoscopy-screened cohort in high-risk regions (Linzhou, Cixian, and Feicheng) of China. Parallel genome-wide association studies of ESCC and GC were conducted using baseline and follow-up cases. Cancer type-specific PRSs were applied using the developed models in Chinese populations. Information on smoking, alcohol use, body mass index, physical activity, and diet was collected to construct a healthy lifestyle score (HLS). Multivariable logistic and Cox models evaluated associations between PRS, HLS, and UGI cancer risk, and risk stratification was assessed by combining PRSs with non-genetic factors. 1050 ESCC and 1015 GC cases were identified, including 203 ESCC and 170 GC incident cases diagnosed during a median follow-up of 5.2 years. A potentially novel GC locus at 6p12.1 (rs72875397) was identified. Higher PRSs were associated with increased risk of ESCC (HR: 1.20; 95% CI: 1.05-1.37) and GC (HR: 1.44; 95% CI: 1.24-1.67). Individuals with high PRS and unfavorable lifestyle had 2.75-fold and 4.18-fold increased risk of ESCC and GC. Adding PRSs to non-genetic models yielded improvements in C-index for ESCC (6.5%) and GC (7.2%). Gradients of benefit from favorable lifestyle were observed across PRS strata, with substantial reductions in cumulative incidence among individuals at high genetic risk (ESCC: from 14.24% to 5.08%; GC: 13.23% to 4.85%). In summary, PRSs improved risk stratification, and favorable lifestyle reduced UGI cancer risk across genetic strata, especially in those with high PRS, supporting risk-informed personalized prevention.