Colorectal Cancer Risk by Genetic Variants in Populations With and Without Colonoscopy History

Background: Polygenic risk scores (PRS), which are derived from results of large genome-wide association studies, are increasingly propagated for colorectal cancer (CRC) risk stratification. The majority of studies included in the large genome-wide association studies consortia were conducted in the United States and Germany, where colonoscopy with detection and removal of polyps has been widely practiced over the last decades. We aimed to assess if and to what extent the history of colonoscopy with polypectomy may alter metrics of the predictive ability of PRS for CRC risk. Methods: A PRS based on 140 single nucleotide polymorphisms was compared between 4939 CRC patients and 3797 control persons of the Darmkrebs: Chancen der Verhutung durch Screening (DACHS) study, a population-based case-control study conducted in Germany. Risk discrimination was quantified according to the history of colonoscopy and polypectomy by areas under the curves (AUCs) and their 95% confidence intervals (CIs). All statistical tests were 2-sided. Results: AUCs and 95% CIs were higher among subjects without previous colonoscopy (AUC = 0.622, 95% CI = 0.606 to 0.639) than among those with previous colonoscopy and polypectomy (AUC = 0.568, 95% CI = 0.536 to 0.601; difference [Delta AUC] = 0.054, P = .004). Such differences were consistently seen in sex-specific groups (women: Delta AUC = 0.073, P = .02; men: Delta AUC = 0.046, P = .048) and age-specific groups (younger than 70 years: Delta AUC = 0.052, P = .07; 70 years or older: Delta AUC = 0.049, P = .045). Conclusions: Predictive performance of PRS may be underestimated in populations with widespread use of colonoscopy. Future studies using PRS to develop CRC prediction models should carefully consider colonoscopy history to provide more accurate estimates.

Automated summary

This study conducted in Germany compared a polygenic risk score (PRS) based on 140 single nucleotide polymorphisms between CRC patients and control persons with or without a history of colonoscopy. The results indicated that the predictive performance of PRS was underestimated in populations with a history of widespread colonoscopy, highlighting the importance of considering colonoscopy history in developing CRC prediction models using PRS to provide more accurate estimates.