Title: Effects of screenings in reducing colorectal cancer incidence and mortality differ by polygenic risk scores

Abstract

Introduction: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, it is unclear whether the reduction in CRC risk may differ by genetic susceptibility. Methods: We evaluated this question in a cohort of 304,740 participants of European descent aged ≥ 50 years. Genetic susceptibility was measured using a polygenic risk score (PRS) constructed with risk variants identified in genome-wide association studies. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of CRC risk. Results: Over a median follow-up of 7.0 years, 2,261 incident CRC cases and 528 CRC deaths were identified. CRC screening was associated with a significantly reduced CRC incidence among individuals with a high (HR, 0.80; 95% CI, 0.71-0.92) and intermediate PRS (0.84, 0.71-0.98) but not among those with a low PRS (1.03, 0.86-1.25; Pinteraction, 0.005). A similar but more evident difference was observed for mortality (Pinteraction, 0.046), with more than 30% reduced mortality observed in the high PRS group (0.69, 0.52- 0.91). Among the younger group (age 50-60 years), CRC screenings were associated with a slightly (but non-significantly) elevated incidence and mortality in the low PRS group but a reduced risk in the high PRS group (Pinteraction, 0.043 [incidence]; 0.092 [mortality]). No significant interaction was observed in the older group (age > 60 years). Conclusion: Individuals with a higher genetic risk benefited more substantially from CRC screenings than those with a lower risk. Our findings suggest that PRS may be used to develop personalized CRC screening to maximize its effect on CRC prevention.