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 to determine starting age for screening, they inadequately incorporate other important unmodifiable risk factors, including polygenic risk score (PRS) and biological sex. In 353,118 average-risk UK Biobank participants, we used family history-stratified Cox models to estimate associations of sex and PRS with CRC incidence, metastasis, and CRC-specific mortality. We 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 family history and 1.42 (95% CI, 1.26-1.61) for those with family history. For each one-standard deviation (SD) increase in PRS, the risk was 1.49 times higher (95% CI, 1.45-1.53) in participants without a family history and 1.42 times higher (95% CI, 1.34-1.51) in those with a family history. The increase in PRS was associated with elevated risks of both metastatic CRC at diagnosis and CRC-specific mortality, indicating delayed diagnosis in high-PRS individuals and highlighting the potential benefit of earlier screening. Consequently, risk-adapted initiation ages ranged from before 40 years for men with a family history in the high-PRS group to after 60 years for women without a family history in the low-PRS group. Our findings demonstrate that the integration of PRS, biological sex, and family history identifies substantial heterogeneity in CRC risk and risk-adapted screening initiation ages.