Background: Colorectal cancer (CRC) has high incidence and associated mortality worldwide. Screening programs are recommended for men and women over 50. Intermediate screens such as fecal immunochemical testing (FIT) select patients for colonoscopy with suboptimal sensitivity. Additional biomarkers could improve the current scenario. Methods: We included 2,893 individuals with a positive FIT test. They were classified as cases when a high-risk lesion for CRC was detected after colonoscopy, whereas the control group comprised individuals with low-risk or no lesions. Sixty-five CRC risk genetic variants were genotyped. Polygenic risk score (PRS) and additive models for risk prediction incorporating sex, age, FIT value and PRS were generated. Results: Risk score was higher in cases compared to controls (per allele OR=1.04; 95%CI 1.02-1.06; P-value< 0.0001). A 2-fold increase in CRC risk was observed for subjects in the highest decile of risk alleles ( {greater than or equal to} 65), compared to those in the first decile ( {less than or equal to} 54) (OR=2.22, 95%CI 1.59-3.12, P-value<0.0001). The model combining sex, age, FIT value and PRS reached the highest accuracy for identifying patients with a high-risk lesion (cross-validated AUROC: 0.64; 95%CI 0.62-0.66). Conclusions: This is the first investigation analyzing PRS in a two-step CRC screening program. PRS could improve current CRC screening, most likely for higher at-risk subgroups. However, its capacity is limited to predict CRC risk status and should be complemented by additional biomarkers. Impact: PRS has capacity for risk stratification of CRC suggesting its potential for optimizing screening strategies alongside with other biomarkers.

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