Precision Colorectal Cancer Screening with Polygenic Risk Score

Colorectal cancer (CRC) is the second most common cancer in women and third most common cancer in men. Genome-wide association studies have identified numerous genetic variants (SNPs) independently associated with CRC. The effects of such SNPs can be combined into a single polygenic risk score (PRS). Stratification of individuals according to PRS could be introduced to primary and secondary prevention. Our aim was to combine risk stratification of a sex-specific PRS model with recommendations for individualized CRC screening. Previously published PRS models for predicting the risk of CRC were collected from the literature. These were validated on the UK Biobank (UKBB) consisting of a total of 458 696 quality-controlled genotypes with 1810 and 1348 prevalent male cases, and 2410 and 1810 incident male and female cases. The best performing sex-specific model was selected based on the AUC in prevalent data and independently validated in the incident dataset. Using Estonian CRC background information, we performed absolute risk simulations and examined the ability of PRS in risk stratifying individual screening recommendations. The best-performing model included 91 SNPs. The C-index of the best performing model in the dataset was 0.613 (SE = 0.007) and hazard ratio (HR) per unit of PRS was 1.53 (1.47 – 1.59) for males. Respective metrics for females were 0.617 (SE = 0.006) and 1.50 (1.44 – 1.58). PRS risk simulations showed that a genetically average 50-year-old female doubles her risk by age 58 (55 in males) and triples it by age 63 (59 in males). In addition, the best performing PRS model was able to identify individuals in one of seven groups proposed by Naber et al. for different coloscopy screening recommendation regimens. We have combined PRS-based recommendations for individual screening attendance. Our approach is easily adaptable to other nationalities by using population-specific background data of other genetically similar populations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement OU Antegenes has received a grant from the EIT Health The Digital Sandbox program and additional Innovation Voucher funding meant for business development of small and medium sized Estonian enterprises. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank: The UK Biobank study was approved by the North West Multi-Centre Research Ethics Committee (UK Biobank reference: 16/NW/0274). All participants provided written informed consent to participate in the UK Biobank study. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual level genotype and phenotype data from UK Biobank can not be explicitly shared. The UK Biobank Resource was used under Application Reference Number 53602. New users can request access to UK Biobank from http://www.ukbiobank.ac.uk/resources/.