Prediction of colorectal cancer risk based on profiling with common genetic variants

Abstract

Increasing numbers of common genetic variants associated with colorectal cancer (CRC) have been identified. Our study aimed to determine whether risk prediction based on common genetic variants might enable stratification for CRC risk. Metaanalysis of 11 genome-wide association studies comprising 16 871 cases and 26 328 controls was performed to capture CRC susceptibility variants. Genetic prediction models with several candidate polygenic risk scores (PRSs) were generated from Scottish CRC case-control studies (6478 cases and 11 043 controls) and the score with the best performance was then tested in UK Biobank (UKBB) (4800 cases and 20 287 controls). A weighted PRS of 116 CRC single nucleotide polymorphisms (wPRS 116) was found with the best predictive performance, reporting a c-statistics of 0.60 and an odds ratio (OR) of 1.46 (95% confidence interval [CI] = 1.41-1.50, per SD increase) in Scottish data set. The predictive performance of this wPRS 116 was consistently validated in UKBB data set with c-statistics of 0.61 and an OR of 1.49 (95% CI = 1.44-1.54, per SD increase). Modeling the levels of PRS with age and sex in the general UK population shows that employing genetic risk profiling can achieve a moderate degree of risk discrimination that could be helpful to identify a subpopulation with higher CRC risk due to genetic susceptibility.

Ability of known colorectal cancer susceptibility SNPs to predict colorectal cancer risk: A cohort study within the UK Biobank

“…In summary, we have found that stratifying colorectal cancer risk by including a PRS with firstdegree family history results in an improved risk prediction compared with using family history alone for a sample that mirrors the general population, for which <15% had a family history. This is in agreement with previous studies that have also shown that a PRS adds substantial value in colorectal cancer risk stratification and explains a sizeable excess risk of colorectal cancer, independent of family history (17,48). Our new data strengthens the argument for clinical application of polygenic risk assessment in the general population, and especially for those without a family history, and supports the expansion of current recommendations that focus only on family history and age as the main criteria for screening.…”

“…There were few incident cases in participants in their 40s. This affected our ability to confirm published evidence(17,48,57), suggesting superior clinical utility in PRS to help detect early-onset colorectal cancer before age 50 years; we observed a not significant trend in the expected direction for the few young age at diagnosis cases (S2 Table). Furthermore, a recently published study (58) has identified, using exome data, 76 participants in the UK biobank who are potential Lynch syndrome carriers, 17 of whom are cases.…”

“…In recent years, an increasing number of susceptibility SNPs have been identified by genomewide association studies, which examine vast numbers of variants across the genome for associations with disease risk (16,17). Although each susceptibility SNP has a weak association with colorectal cancer risk, the cumulative association of many SNPs combined as a polygenic risk score (PRS) can result in a substantial risk gradient (in both directions) and is potentially an effective risk stratification method (14,18).…”

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

“…In the past 2 decades, genome-wide association studies (GWASs) have identified a rapidly increasing number of single nucleotide polymorphisms (SNPs) that are independently associated with the risk of colorectal cancer (CRC) ( 1‐8 ). Recent studies have shown that polygenic risk scores (PRS) built from these SNPs may be useful for CRC risk prediction and risk stratification for personalized screening ( 9 , 10 ). Furthermore, a prior study suggested that people with high genetic risk are most likely to benefit from the targeted CRC screening strategies ( 11 ).…”

Identification of known and novel familial cancer genes in Swedish colorectal cancer families

“…Large GWAS have identified more than 100 loci associated with an increased risk of CRC. [7][8][9] However, most of the loci confer low risk and do not explain the seemingly increased risk in cancer families. Therefore, when massive parallel sequencing became possible, families have been used for studies using whole-exome sequencing (WES) and whole genome sequencing (WGS) to find the responsible genes.…”