Upper gastrointestinal (UGI) cancers, mainly esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), represent a major health burden in China. More than half of global cases occur in China. Because early-stage disease often presents with nonspecific symptoms, many patients are diagnosed at advanced stages when prognosis is poor. Endoscopic screening has been shown to improve early detection and survival, but its invasive nature and cost limit large-scale implementation. Identifying individuals at high risk and prioritizing those most likely to benefit from screening and prevention remains an important challenge.
UGI cancer develops through a complex process influenced by both genetic susceptibility and environmental exposures. Although previous studies have identified multiple genetic variants and lifestyle-related risk factors, their combined effects and potential application in risk stratification within screening populations remain unclear.
To address this question, researchers conducted a study among 5,556 participants enrolled in a multicenter endoscopic screening program in high-risk regions of UGI cancer in China. Participants were followed prospectively. The team performed genome-wide association studies for ESCC and GC and evaluated genetic susceptibility using previously developed polygenic risk scores (PRSs). Information on smoking, alcohol consumption, body mass index, physical activity, and dietary habits was used to construct a healthy lifestyle score. The study assessed the independent and joint contributions of genetic risk and lifestyle to cancer risk and evaluated whether genetic information could improve risk prediction of conventional risk factors.
The researchers identified a potential new susceptibility locus for GC located at chromosome 6p12.1. They also found that PRS improved risk stratification in the screening population. When PRSs were added to traditional risk factor models, the C statistics of ESCC and GC risk prediction models increased by 6.5% and 7.2%, respectively. The study also showed that genetic risk and lifestyle factors contributed independently to UGI cancer risk. Individuals with both high genetic risk and an unfavorable lifestyle had 2.75-fold and 4.18-fold increased risk of ESCC and GC compared with those with low genetic risk and a healthy lifestyle. Maintaining a healthy lifestyle was associated with reduced cancer risk across different levels of genetic susceptibility, with particularly strong benefits observed among individuals at high genetic risk.
These findings suggest that integrating genetic risk information with lifestyle factors may help improve risk stratification and identify individuals who would benefit most from screening and targeted prevention. The results provide evidence supporting risk-informed strategies for UGI cancer prevention and more efficient allocation of screening resources in high-risk regions.
The study was led by Professor Wenqiang Wei and Professor Shaoming Wang from the National Cancer Center and Cancer Hospital, Chinese Academy of Medical Sciences. Feifan He was the first author of the study.
