Prostate cancer risk prediction using polygenic hazard scores in Nordic populations

Context SummaryO_ST_ABSKey ObjectiveC_ST_ABSCan polygenic hazard scores accurately predict prostate cancer disease risk and age at diagnosis in Nordic populations? Knowledge GeneratedPolygenic hazard score PHS601 stratified prostate cancer risk with a towfold increase per standard deviation increase in two Norwegian populations (N = 17,538). The top 1.7% of scores conferred 8.7-fold higher risk compared with median risk, exceeding the risk associated with pathogenic HOXB13 variants. PURPOSEMore accurate risk prediction is needed for prostate cancer (PCa) to identify individuals at greatest risk of early-onset and clinically-significant disease. Current screening paradigms, such as prostate-specific antigen screening, pose risks due to over-diagnosis and over-treatment of indolent disease. Polygenic hazard scores (PHS) can predict age-at-diagnosis of PCa and are being tested in prospective clinical screening trials. We evaluated the performance of the latest PHS model for PCa (PHS601) in two Norwegian populations. MATERIALS AND METHODSWe assessed PHS601 performance in two Norwegian cohorts (N = 14,688 and N = 2,850) for predicting age-at-diagnosis of PCa and aggressive PCa. In a subset with whole-genome sequencing (N = 526), we compared PHS601 performance to screening for rare pathogenic variants, including HOXB13. RESULTSPHS601 effectively stratified participants by risk in both cohorts (HR per SD = 1.87 [1.78, 1.96] and 2.02 [1.83, 2.23]). Among individuals with whole-genome sequencing, the top 1.7% of PHS values conferred 8.7-fold higher risk than the median (HR = 8.75 [5.02, 14.77]), exceeding the risk associated with HOXB13 pathogenic variants (HR = 3.77 [1.75, 8.11]; 1.7% carrier frequency). CONCLUSIONThese findings support the potential utility of PHS601 in a precision screening paradigm for PCa.