Prediction of Colorectal Cancer Risk Based on Profiling with Common Genetic Variants

Increasing numbers of common genetic variants associated with colorectal cancer (CRC) have been identified. This study aimed to determine whether risk prediction based on common genetic variants might enable stratification for CRC risk. Meta-analysis of eleven genome-wide association studies (GWAS) comprising 16,871 cases and 26,328 controls was performed to capture CRC susceptibility variants. Genetic prediction models with several candidate polygenic risk scores (PRSs) were generated from Scottish CRC case-control studies (6478 cases and 11,043 controls), and the score with the best performance was then tested in UK Biobank (4800 cases and 20,287 controls). A weighted PRS of 116 CRC SNPs (wPRS116 ) was found with the best predictive performance, reporting a c-statistics of 0.60 and an odds ratio (OR) of 1.46 (95%CI: 1.41-1.50, per SD increase) in Scottish dataset. The predictive performance of this wPRS116 was consistently validated in UK Biobank dataset with c-statistics of 0.61 and an OR of 1.49 (95%CI: 1.44-1.54, per SD increase). Modelling the levels of PRS with age and sex in the general UK population shows that employing genetic risk profiling can achieve a moderate degree of risk discrimination that could be helpful to identify a subpopulation with higher CRC risk due to genetic susceptibility. This article is protected by copyright. All rights reserved.