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".

The authors have declared no competing interest.

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.

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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).

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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 https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access. Further information is available from the corresponding author upon request.