UK Biobank analysis of integrating polygenic risk score, sex, and family history to personalize the initial screening age for colorectal cancer

While current colorectal cancer (CRC) screening guidelines consider family history (FH) to determine starting age for screening, they inadequately incorporate other important unmodifiable factors, including polygenic risk score (PRS) and biological sex. Analysis of 353,118 average-risk UK Biobank participants used FH-stratified Cox models to estimate associations of sex and PRS with CRC incidence, metastasis, and CRC-specific mortality. The authors translated risk differences into risk-adapted initiation screening ages using both risk advancement period (RAP) and absolute 10-year cumulative risk. Men had a higher risk of CRC compared to women , with HRs of 1.41 (95% CI 1.33-1.50) for those without FH and 1.42 (1.26-1.61) for those with FH. For each one-SD increase in PRS, the risk was 1.49 times higher (95% CI 1.45-1.53) in participants without FH and 1.42 times higher (1.34-1.53) in those with FH. The increase in PRS was associated with elevated risk of both metastatic CRC at diagnosis an CRC-specific mortality, indicating delayed diagnosis in high-PRS individuals and highlighting the potential benefit of earlier screening. Consequently, risk-adapted initiation of screening ages ranged from before 40 years for men with FH in the high-PRS group to after 60 years for women without FH in the low-PRS group. The authors conclude that these findings demonstrate that integration of PRS, biological sex, and FH identifies substantial heterogeneity in CRC risk and risk-adapted screening initiation ages (graphical abstract).