Genetic prediction of colorectal cancer risk in six major ancestries provides insights to streamline practice screening guidelines

ABSTRACT Background and objective Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide. Early identification of high-risk individuals allows targeted prevention and early detection. Design We constructed a polygenic risk score (PRS) for CRC risk using data from 1,448,354 individuals (103,401 cases). We evaluated its performance for identifying high-risk individuals in 6 major ancestries. Results The PRS was strongly associated with CRC risk in Europeans (OR per SD =2.13, 95%CI=1.98-2.28), Africans (OR=1.35, 95%CI=1.11-1.64), Hispanics (OR=1.97, 95%CI =1.48-2.61), East Asians (OR=1.98, 95%CI=1.35-2.91), South Asians (OR=1.85, 95%CI=1.44 - 2.37), and Middle Easterners (OR=3.10, 95%CI=1.38-6.95). Europeans in the top 10% genetic risk had 14-fold and 5-fold higher CRC risks compared to the bottom 10% (OR=13.50, 95%CI=8.67-21.00), and average (20-70%) risk groups (OR=4.64, 95%CI=3.89-5.52), respectively. The CRC risk in the top 10% individuals was equivalent to having three affected first degree relatives with CRC diagnosed at any age. Genetically high-risk individuals developed CRC up to 15 years earlier than the average. The PRS was strongly associated with early onset CRC risk e.g. in AFR (OR=3.22, 95%CI=1.79-5.81), and improved its prediction e.g. by 9% beyond clinical predictors in EUR. Conclusion A comprehensive genetic prediction of CRC risk provides insights that could streamline screening and prevention guidelines. What is already known on this topic - Current screening and prevention programs for CRC rely on clinical assessments of future risk. We investigated whether a genetic test (PRS) can identify high-risk individuals to be prioritised for screening. What this study adds - The PRS identified the top 10% of individuals with 5-fold higher CRC risk and developed CRC 15 years earlier than the average, and improved the prediction of early-onset CRC by 9%. - Individuals in the top 10% PRS (high genetic risk) with no family history of CRC had the same risk as those with at least three first degree relatives with CRC diagnosed at any age. How this study might affect research, practice or policy - Our findings provide comprehensive evidence to support potential integration of polygenic screening into clinical practice guidelines for CRC screening, early identification and prevention across different populations or ancestries