Polygenic hazard score is associated with prostate cancer in multi-ethnic populations
Authors: Huynh-Le Minh-Phuong , Fan Chun Chieh , Karunamuni Roshan , Thompson Wesley K , Martinez Maria Elena , Eeles Rosalind A , Kote-Jarai Zsofia , Muir Kenneth ,   UKGPCS collaborators, Schleutker Johanna , Pashayan Nora , Batra Jyotsna ,   APCB (Australian Prostate Cancer BioResource), Grönberg Henrik , Neal David E , Donovan Jenny L , Hamdy Freddie C , Martin Richard M , Nielsen Sune F , Nordestgaard Børge G , Wiklund Fredrik , Tangen Catherine M , Giles Graham G , Wolk Alicja , Albanes Demetrius , Travis Ruth C , Blot William J , Zheng Wei , Sanderson Maureen , Stanford Janet L , Mucci Lorelei A , West Catharine M L , Kibel Adam S , Cussenot Olivier , Berndt Sonja I , Koutros Stella , Sørensen Karina Dalsgaard , Cybulski Cezary , Grindedal Eli Marie , Menegaux Florence , Khaw Kay-Tee , Park Jong Y , Ingles Sue A , Maier Christiane , Hamilton Robert J , Thibodeau Stephen N , Rosenstein Barry S , Lu Yong-Jie , Watya Stephen , Vega Ana ,   NC-LA PCaP Investigators,   The IMPACT Study Steering Committee and Collaborators, Kogevinas Manolis , Penney Kathryn L , Huff Chad , Teixeira Manuel R , Multigner Luc , Leach Robin J , Cannon-Albright Lisa , Brenner Hermann , John Esther M , Kaneva Radka , Logothetis Christopher J , Neuhausen Susan L , Ruyck Kim De , Pandha Hardev , Razack Azad , Newcomb Lisa F ,   Canary PASS Investigators, Fowke Jay , Gamulin Marija , Usmani Nawaid , Claessens Frank , Gago-Dominguez Manuela , Townsend Paul A , Bush William S , Srivastava Shiv , Roobol Monique J , Parent Marie-Élise , Hu Jennifer J ,   The Profile Study Steering Committee, Mills Ian G , Andreassen Ole A , Dale Anders M , Seibert Tyler M ,   The PRACTICAL Consortium
Published: November 2019

AbstractObjectivesA polygenic hazard score (PHS1)—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.DesignPHS1 was adapted for compatibility with genotype data from the OncoArray project (PHS2) and tested for association with age at PCa diagnosis, at aggressive PCa diagnosis, and at PCa death.SettingMultiple international institutions.ParticipantsMen with available OncoArray data from the PRACTICAL consortium who were not included in PHS1 development/validation.Main Outcomes and MeasuresPHS2 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.Results80,491 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. PHS2 had 46 polymorphisms: 24 directly genotyped and 22 acceptable proxies (r2 ≥0.94). PHS2 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). PHS2 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 80th and 20th 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.ConclusionsPHS2 is strongly associated with age at PCa diagnosis in a multi-ethnic dataset. PHS2 stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal PCa.Summary boxesWhat is already known on this topicGenetic 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 ancestryA polygenic hazard score was previously associated with age at prostate cancer diagnosis and improved PCa screening accuracy in EuropeansPerformance of the polygenic hazard score in multi-ethnic populations is unknownWhat this study addsIn 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.