IDDF2024-ABS-0187 Polygenic risk score, healthy lifestyle score, and colorectal cancer risk: a prospective cohort study

<h3>Background</h3> 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. <h3>Methods</h3> We included 51,165 participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. A polygenic risk score was created based on 93 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. <h3>Results</h3> During a median follow-up of 12.21 years, 657 new CRC cases were recorded. 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 = 1.44 and 2.15, respectively; IDDF2024-ABS-0187 Figure 1. Effect of genetic and lifestyle factors on the risk of incident colorectal cancer in the PLCO cohort. (A) The cumulative incidence of colorectal cancer in low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk groups in the PLCO cohort. (B) The cumulative incidence of colorectal cancer in participants who had a favorable lifestyle (adopted at least four healthy lifestyle factors), an intermediate lifestyle (adopted two or three healthy lifestyle factors), and an unfavorable lifestyle (adopted none or one healthy lifestyle factor) in the PLCO cohort). 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 51% 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 2.19% (IDDF2024-ABS-0187 Figure 2. Ten-year colorectal cancer absolute risk according to lifestyle and genetic risk in the PLCO cohort), respectively. <h3>Conclusions</h3> Our findings suggest that adherence to a healthy lifestyle holds promise to reduce the genetic impact on CRC risk.