Fecal immunochemical tests (FITs) are increasingly used as noninvasive screening tests in colorectal cancer (CRC) screening programs. Polygenic risk scores (PRS) are increasingly propagated for risk stratification in CRC screening. We aimed to assess the potential of combining FIT results and PRS to enhance diagnostic accuracy of detecting advanced neoplasia (AN) compared to using FIT results alone. Of 10,362 participants of screening colonoscopy in Southern Germany who conducted either one of two quantitative FITs, genotyping was done in all participants with advanced neoplasia (CRC or advanced adenoma) and a random subset of controls. Among 5,306 individuals, a PRS was calculated based on the number of risk alleles in 140 single nucleotide polymorphisms. Partial areas under the receiver operating characteristics (ROC) curves (pAUCs) were computed for FIT and PRS alone and combined, focusing on a specificity range of 100%-80%. Both FITs showed similar performance characteristics with pAUCs (95%CIs) of 0.661 (0.625-0.698) (Ridascreen Hemoglobin) and 0.682 (0.661-0.701) (FOB Gold) for AN detection. PRS alone reached a pAUC (95%CI) of 0.524 (0.499-0.550) and 0.530 (0.516-0.545), respectively, and its addition to FIT did not improve pAUCs (0.659 (0.622-0.697) and 0.667 (0.650-0.687), respectively). This finding was confirmed by investigating sensitivities at fixed specificities at 85%, 90% and 95%. Partial AUCs also did not improve when adding the weighted PRS to FIT instead of the unweighted PRS. In summary, the combination with PRS did not improve diagnostic accuracy of FIT-based screening in a large asymptomatic CRC screening population from South-Western Germany.

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