Polygenic hazard score is associated with prostate cancer in multi-ethnic populations

Abstract Objectives A polygenic hazard score (PHS 1 )—weighted sum of 54 single-nucleotide polymorphism genotypes—was previously associated with age at prostate cancer (PCa) diagnosis and improved PCa screening accuracy in Europeans. Performance in more diverse populations is unknown. We evaluated PHS association with PCa in multi-ethnic populations. Design PHS 1 was adapted for compatibility with genotype data from the OncoArray project (PHS 2 ) and tested for association with age at PCa diagnosis, at aggressive PCa diagnosis, and at PCa death. Setting Multiple international institutions. Participants Men with available OncoArray data from the PRACTICAL consortium who were not included in PHS 1 development/validation. Main Outcomes and Measures PHS 2 was tested via Cox proportional hazards models for age at PCa diagnosis, age at aggressive PCa diagnosis (any of: Gleason score ≥7, stage T3-T4, PSA≥10 ng/mL, nodal/distant metastasis), and age at PCa-specific death. Results 80,491 men of various self-reported race/ethnicities were included (30,575 controls, 49,916 PCa cases; genetic ancestry groups: 71,856 European, 6,253 African, 2,382 Asian). Median age at last follow-up was 70 years (IQR 63-76); 3,983 PCa deaths, 5,806 other deaths, 70,702 still alive. PHS 2 had 46 polymorphisms: 24 directly genotyped and 22 acceptable proxies (r 2 ≥0.94). PHS 2 was associated with age at PCa diagnosis in the multi-ethnic dataset (z=54, p<10 -16 ) and in each genetic ancestry group: European (z=56, p<10 -16 ), Asian (z=47, p <10 -16 ), African (z=29, p <10 -16 ). PHS 2 was also associated with age at aggressive PCa diagnosis in each genetic ancestry group (p<10 -16 ) and with age of PCa death in the full dataset ( p <10 -16 ). Comparing the 80 th and 20 th percentiles of genetic risk, men with high PHS had hazard ratios of 5.3 [95% CI: 5.0-5.7], 5.9 [5.5-6.3], and 5.7 [4.6-7.0] for PCa, aggressive PCa, and PCa-specific death, respectively. Within European, Asian, and African ancestries, analogous hazard ratios for PCa were 5.5 [5.2-5.9], 4.5 [3.2-6.3], and 2.5 [2.1-3.1], respectively. Conclusions PHS 2 is strongly associated with age at PCa diagnosis in a multi-ethnic dataset. PHS 2 stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal PCa. Summary boxes What is already known on this topic Genetic risk stratification can identify men with greater predisposition for developing prostate cancer, but these risk models may worsen health disparities, as most have only been validated for men of European ancestry A polygenic hazard score was previously associated with age at prostate cancer diagnosis and improved PCa screening accuracy in Europeans Performance of the polygenic hazard score in multi-ethnic populations is unknown What this study adds In a dataset from 80,491 men of various self-reported race/ethnicities, the polygenic hazard score was associated with age at prostate cancer diagnosis, aggressive prostate cancer diagnosis, and prostate cancer death. PHS stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal prostate cancer.

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