Polygenic Risk Score, Healthy Lifestyle Score, and Colorectal Cancer Risk: A Prospective Cohort Study

Abstract Background: Both genetic factors and lifestyle play a critical role in colorectal cancer, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unclear. Methods: We included 51,171 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer cohort. A polygenic risk score was created based on 205 genetic variants associated with colorectal cancer, and a healthy lifestyle score was constructed based on six lifestyle factors. Cox regression models were used to evaluate the association of genetic and lifestyle factors with colorectal cancer incidence. Results: Compared with individuals at low genetic risk (the lowest 20%), those with intermediate genetic risk (20%–80%) and high genetic risk (the highest 20%) had a significantly increased risk of colorectal cancer (HR = 1.71 and 2.52, respectively). Compared with participants with a favorable lifestyle (scoring 4–6), those with an unfavorable lifestyle (scoring 0 or 1) had a 47% higher risk of colorectal cancer. Moreover, participants with a high genetic risk and a favorable lifestyle had a 45% lower risk of colorectal cancer than those with a high genetic risk and an unfavorable lifestyle, with their 10-year absolute risks of 1.29% and 2.07%, respectively. Conclusions: Our findings suggest that adherence to a healthy lifestyle holds promise to reduce the genetic impact on colorectal cancer risk. Impact: This study indicates that modifiable lifestyle factors play an important role in colorectal cancer prevention, providing new insights for personalized prevention strategies.