Using risk advancement periods to derive starting ages of colorectal cancer screening according to sex and polygenic risk score: Results from the UK Biobank

Objective Polygenic risk scores (PRSs) derived from genome-wide association studies are strong predictors of colorectal cancer (CRC) risk. We applied the straightforward approach of risk advancement periods (RAPs) to derive risk-adapted starting ages of CRC screening according to sex and PRS in the UK Biobank. Methods Among 242,779 participants (40-69 years; no previous CRC screening; no family history of CRC), we assessed associations of sex and a PRS with CRC risk and mortality using Cox regression models. Hazard ratios (HRs) were translated to RAPs to quantify how many years of age earlier men and women in defined PRS deciles reach comparable risks as those in the reference group (5th and 6th PRS deciles). Results During a median follow-up of 11.2 and 12.8 years, 2,714 participants were diagnosed with CRC and 758 died from CRC, respectively. HRs (95% CIs) of CRC risk were 1.57 (1.46, 1.70) for men versus women and ranged from 0.51 (0.41, 0.62) to 2.29 (2.01, 2.62) across PRS deciles compared to the reference. RAPs (95% CI) were 5.6 (4.6, 6.6) years for men versus women, and ranged from -8.4 (-11.0, -5.9) to 10.3 (8.5, 12.1) years across PRS deciles compared to the reference. Risk-adapted starting ages would vary by 24 years between men in the highest PRS decile and women in the lowest PRS decile. Very similar results were obtained regarding CRC mortality. Conclusion Consideration of sex and a standard PRS alone could have far-reaching implications for starting ages of CRC screening in the “average risk population”. What is already known on this topic What this study adds How this study might affect research, practice or policy ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported in part by the German Cancer Aid (Deutsche Krebshilfe, grant no. 70113330). The sponsors had no role in the study design and in the collection, analysis, and interpretation of data. ### 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: The UK Biobank study has obtained approval from the North West Multi-center Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval (renewed approval in 2021: 21/NW/0157). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This work used data provided by patients and collected by the NHS as part of their care and support. The UK Biobank is an open-access resource and bona fide researchers can apply to use the UK Biobank dataset by registering and applying at . Further information is available from the corresponding author upon request.