Pan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction

TLDR

Cancer risk arises from a complex interplay of environmental and heritable factors, and polygenic risk scores offer a personalized genetic susceptibility profile that can be leveraged for disease prediction. The study aims to quantify the added predictive value of integrating cancer‑specific PRS with family history and modifiable risk factors for 16 cancers. The authors used data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases) to assess this integration. Incorporating PRS measurably improves prediction accuracy for most cancers, with the top 20 % of the PRS distribution accounting for 4.0 % to 30.3 % of incident cases, and stratification by PRS levels reveals divergent 5‑year risk trajectories beyond family history and modifiable factors, underscoring the potential of integrated genetic risk scores for cancer risk assessment.

Abstract

Abstract Cancer risk is determined by a complex interplay of environmental and heritable factors. Polygenic risk scores (PRS) provide a personalized genetic susceptibility profile that may be leveraged for disease prediction. Using data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases), we quantify the added predictive value of integrating cancer-specific PRS with family history and modifiable risk factors for 16 cancers. We show that incorporating PRS measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially. We also demonstrate that stratifying on levels of PRS identifies significantly divergent 5-year risk trajectories after accounting for family history and modifiable risk factors. At the population level, the top 20% of the PRS distribution accounts for 4.0% to 30.3% of incident cancer cases, exceeding the impact of many lifestyle-related factors. In summary, this study illustrates the potential for improving cancer risk assessment by integrating genetic risk scores.