Combining genome-wide polygenic scores with registry data for colorectal cancer risk-based screening

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BACKGROUND: Polygenic risk scores (PRS) show potential for risk-based colorectal cancer (CRC) screening, but their utility must be assessed across diverse ancestries and tumour characteristics and compared with the current standard, the faecal immunochemical test (FIT). DESIGN: The cohort included 112,204 individuals from the Copenhagen Hospital Biobank (8995 with adenoma and 9246 with CRC), all with linked genetic and health registry data. A subset (N = 20,658) also had FIT results. CRC PRSs were evaluated for their association with lifetime adenoma and CRC risk and their predictive value individually and combined with FIT. RESULTS: PRS stratified population-calibrated lifetime adenoma and CRC risk independently of ancestry and sex. Individuals with a high PRS reached the incidence of low-PRS individuals up to 10 years earlier, between ages 45-60. PRS stratified risk across tumour location and histologies but showed no association among individuals with deficient mismatch repair tumours (N = 623). Combining PRS with FIT did not meaningfully improve prediction of adenoma or CRC at first screening, negative colonoscopy outcomes among FIT-positive participants, or outcomes within 2 years after a negative FIT. CONCLUSION: PRS stratifies lifetime adenoma and CRC risk and may inform risk-based screening initiation and intensity but adds limited predictive value when combined with FIT.

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