• Nanjing Medical University, Nanjing, China.
• National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

BACKGROUND: Both genetic factors and lifestyle play a critical role in colorectal cancer (CRC), 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 PLCO cohort. A polygenic risk score was created based on 205 genetic variants associated with CRC, 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 CRC 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 CRC (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 CRC. Moreover, participants with a high genetic risk and a favorable lifestyle had a 45% lower risk of CRC 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 CRC risk.

IMPACT: This study indicates that modifiable lifestyle play an important role in CRC prevention, providing new insights for personalized prevention strategies.