Effects of Screenings in Reducing Colorectal Cancer Incidence and Mortality Differ by Polygenic Risk Scores

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 and older. Genetic susceptibility was measured using a polygenic risk score (PRS) constructed with risk variants identified in genomewide association studies. Cox models were used to estimate hazard ratios and 95% confidence intervals 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 (hazard ratio, 0.80; 95% confidence interval, 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; P(interaction), 0.005). A similar but more evident difference was observed for mortality (P(interaction), 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 nonsignificantly) elevated incidence and mortality in the low PRS group but a reduced risk in the high PRS group (P(interaction), 0.043 [incidence]; 0.092 [mortality]). No significant interaction was observed in the older group (age > 60 years). DISCUSSION: 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.