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

Abstract

Background Polygenic risk scores (PRS), which are derived from results of large genome-wide association studies (GWAS), are increasingly propagated for colorectal cancer (CRC) risk stratification. The majority of studies included in the large GWAS 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 cases and 3797 controls of the 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 two-sided. Results AUCs (95% CIs) were higher among subjects without previous colonoscopy (0.622 [0.606–0.639]) than among those with previous colonoscopy and polypectomy (0.568 [0.536–0.601], difference [Δ AUC] = 0.054, p = .004). Such differences were consistently seen in sex-specific groups (women: Δ AUC = 0.073, p = .02; men: Δ AUC = 0.046, p = .048) and age-specific groups (<70 years: Δ AUC = 0.052, p = .07; ≥70 years: Δ 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 in order to provide more accurate estimates.

Polygenic Risk Score for Defining Personalized Surveillance Intervals After Adenoma Detection and Removal at Colonoscopy

“…Moreover, the genetic risk was represented by a PRS based on 140 SNPs discovered by a recent large GWAS, which showed a better predictive performance compared with a prior PRS with approximately 60 SNPs. 8,29 However, several limitations also require careful consideration and discussion. First, although we carefully adjusted for a large number of risk and preventive factors of CRC, we cannot rule out residual confounding and selection bias in this case-control study.…”

Non‐steroidal anti‐inflammatory drugs, polygenic risk score and colorectal cancer risk

“…DNA was extracted from blood samples (in 99.1% of participants) or from buccal cells (in 0.9% of participants). Information about genotyping and imputation of missing genotypes for the study population has been described in detail previously 20,24 . In brief, the following four genotyping arrays were used: Illumina HumanCytoSNP for 49.5% of participants, Illumina HumanOmniExpress for 19.5% of participants, Illumina Infinium OncoArray for 16.8% of participants and the Illumina Infinium Global Screening Array for 14.2% of participants.…”

“…The score was calculated as the sum of risk alleles of the respective variants (0, 1 or 2 copies of the risk allele for genotyped SNPs; imputed dosages for imputed SNPs). Full details of derivation of PRS have been published recently 20,24,26–29 …”

Physical activity, polygenic risk score, and colorectal cancer risk

“…Table S1 provides information about genotyping and imputation of missing genotypes that have been reported elsewhere 19,24 . The PRS in the current analysis aggregates information from 140 CRC‐related loci identified in a recent genome‐wide association study (Table S2).…”

“…Table S1 provides information about genotyping and imputation of missing genotypes that have been reported elsewhere. 19 , 24 The PRS in the current analysis aggregates information from 140 CRC‐related loci identified in a recent genome‐wide association study (Table S2 ). 4 It was calculated by summing risk alleles of the respective variants (0, 1, or 2 copies per risk allele for genotyped loci; imputed dosages for imputed loci).…”