Abstract A010: Performance of colorectal cancer genetic risk scores and its utility in recall by genotype in East Asians

Abstract Background: Polygenic risk scores (PRSs) have potential for clinical utility. However, their performance and predictability have been inconsistent. This study aimed to assess the performance and predictability of PRSs for colorectal cancer (CRC) in East Asians and use PRSs to perform a recall by genotype (RbG) to assess the causality. Methods: Genome-wide association summary statistics for PRSs construction were obtained from Biobank Japan (BBJ), Korean Genomic Epidemiology Study (KoGES), and East Asian Colorectal Cancer Consortium (EACCC). The target cohort for PRSs development were obtained from Taiwan and Taipei Medical University Biobanks. PRSs were constructed using PRIScie. Individuals with high and low PRSs for cigarette smoking and alcohol consumption were classified as “high risk” and “low risk,” respectively and used in RbG. We validated our RbG findings using a Mendelian randomization (MR). Results: The most predictive PRSs were derived from EACCC and individuals in the top 10% of the decile had an increased risk of CRC (odds ratio [OR] = 2.11, 95% confidence interval [CI] = 1.44-3.12, P = 0.000149) compared to those in the bottom decile. Using RbG, we found that cigarette smoking (OR = 1.61, 95% CI = 1.20-2.16, P = 0.00136) and alcohol consumption (OR = 1.85, 95%CI = 1.09-3.04, P = 0.01871) to be causally associated with CRC. Moreover, our RbG findings were replicated MR approaches. Conclusion: PRSs derived from EACCC performed better than PRSs derived from BBJ and a meta-analysis of the KoGES and BBJ. Our RbG and MR analyses found cigarette smoking and alcohol consumption to be causally associated with CRC. Citation Format: Abram Bunya Kamiza, Chih-Ching Yeh. Performance of colorectal cancer genetic risk scores and its utility in recall by genotype in East Asians [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A010.