Prognostic evaluation of polygenic risk score underlying pan-cancer analysis: evidence from two large-scale cohorts

BACKGROUND: Polygenic risk score (PRS) has been demonstrated to be effective in identifying individuals at high risk of developing cancer, but its prognostic value remains unclear. METHODS: We constructed site-specific PRSs by aggregating the risk effect of independent variants derived from previous genome-wide association studies (GWASs) across 17 cancer types. The Cox proportional hazards model was used to evaluate the association of each PRS with cancer survival, leveraging data from two prospective European cohorts, namely the UK Biobank involving 19,628 incident cases and The Cancer Genome Atlas involving 7079 prevalent cases. The combined PRS (CPRS), determined by merging site-specific PRSs, was further used to assess the prognostic effect of PRS on overall cancer in a sex-specific manner. FINDINGS: We discovered that the cancer risk-related PRS was associated with neither overall survival (OS) nor cancer-specific survival (CSS) of each site-specific cancer with an underlying false discovery rate (FDR) P > 0.05, as evidenced by consistent findings from the two cohorts. Furthermore, the fixed-effect meta-analysis of the two cohorts provided no evidence to support for an association between CPRS and overall cancer survival in both males [OS: hazard ratio (HR)(meta) = 1.00, P(meta) = 0.760; CSS: HR(meta) = 1.01, P(meta) = 0.447] and females (OS: HR(meta) = 0.97, P(meta) = 0.067; CSS: HR(meta) = 0.96, P(meta) = 0.054). Similar results were observed across multiple sensitivity analyses. INTERPRETATION: Our findings indicate that the risk-specific PRS might not be a clinically useful tool in cancer prognosis prediction and further studies focusing on the development of polygenic prognostic score are warranted. FUNDING: This project was funded by the 10.13039/501100001809National Natural Science Foundation of China (82173601 and 82073631), and 10.13039/501100012246Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).