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

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).

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.

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.

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.