Cancer site–specific polygenic risk scores (PRS) effectively identify individuals at high risk of individual cancers, but the effectiveness of PRS on overall cancer risk assessment and the extent to which a high genetic risk of overall cancer can be offset by a healthy lifestyle remain unclear. Here, we constructed an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific PRSs. Lifestyle was determined according to smoking, alcohol consumption, physical activity, body mass index, and diet. Cox regression by sex was used to analyze associations of genetic and lifestyle factors with cancer incidence using UK Biobank data (N = 442,501). Compared with participants at low genetic risk (bottom quintile of CPRS), those at intermediate (quintiles 2 to 4) or high (top quintile) genetic risk had HRs of 1.27 (95% confidence interval, 1.21–1.34) or 1.91 (1.81–2.02) for overall cancer, respectively, for men, and 1.21 (1.16–1.27) or 1.62 (1.54–1.71), respectively, for women. A joint effect of genetic and lifestyle factors on overall cancer risk was observed, with HRs reaching 2.99 (2.45–3.64) for men and 2.38 (2.05–2.76) for women with high genetic risk and unfavorable lifestyle compared with those with low genetic risk and favorable lifestyle. Among participants at high genetic risk, the standardized 5-year cancer incidence was significantly reduced from 7.23% to 5.51% for men and from 5.77% to 3.69% for women having a favorable lifestyle. In summary, individuals at high genetic risk of overall cancer can be identified by CPRS, and risk can be attenuated by adopting a healthy lifestyle.
A new indicator of cancer polygenic risk score measures genetic risk for overall cancer, which could identify individuals with high cancer risk to facilitate decision-making about lifestyle modifications for personalized prevention.