Prostate cancer risk stratification improved across multiple ancestries with new polygenic hazard score
Authors: Huynh-Le Minh-Phuong , Karunamuni Roshan , Fan Chun Chieh , Asona Lui , Thompson Wesley K , Martinez Maria Elena , Eeles Rosalind A , Kote-Jarai Zsofia , Muir Kenneth R , Lophatananon Artitaya , Schleutker Johanna , Pashayan Nora , Batra Jyotsna , Grönberg Henrik , Neal David E , Nordestgaard Børge G , Tangen Catherine M , MacInnis Robert J , Wolk Alicja , Albanes Demetrius , Haiman Christopher A , Travis Ruth C , Blot William J , Stanford Janet L , Mucci Lorelei A , West Catharine M L , Nielsen Sune F , Kibel Adam S , Cussenot Olivier , Berndt Sonja I , Koutros Stella , Sørensen Karina Dalsgaard , Cybulski Cezary , Grindedal Eli Marie , Menegaux Florence , Park Jong Y , Ingles Sue A , Maier Christiane , Hamilton Robert J , Rosenstein Barry S , Lu Yong-Jie , Watya Stephen , Vega Ana , Kogevinas Manolis , Wiklund Fredrik , Penney Kathryn L , Huff Chad D , Teixeira Manuel R , Multigner Luc , Leach Robin J , Brenner Hermann , John Esther M , Kaneva Radka , Logothetis Christopher J , Neuhausen Susan L , De Ruyck Kim , Ost Piet , Razack Azad , Newcomb Lisa F , Fowke Jay H , Gamulin Marija , Abraham Aswin , Claessens Frank , Castelao Jose Esteban , Townsend Paul A , Crawford Dana C , Petrovics Gyorgy , van Schaik Ron HN , Parent Marie-Élise , Hu Jennifer J , Zheng Wei , Mills Ian G , Andreassen Ole A , Dale Anders M , Seibert Tyler M ,   UKGPCS collaborators,   APCB (Australian Prostate Cancer BioResource),   NC-LA PCaP Investigators,   The IMPACT Study Steering Committee and Collaborators,   Canary PASS Investigators,   The Profile Study Steering Committee,   The PRACTICAL Consortium
Published: August 2021

AbstractIntroductionProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.