| Title: |
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; Martinez, Maria Elena; Eeles, Rosalind; Kote-Jarai, Zsofia; Muir, Kenneth; Lophatananon, Artitaya; Schleutker, Johanna; Pashayan, Nora; Batra, Jyotsna; Grönberg, Henrik; Neal, David; Nordestgaard, Børge; Tangen, Catherine; MacInnis, Robert; Wolk, Alicja; Albanes, Demetrius; Haiman, Christopher; Travis, Ruth; Blot, William; Stanford, Janet; Mucci, Lorelei; West, Catharine; Nielsen, Sune; Kibel, Adam; Cussenot, Olivier; Berndt, Sonja; Koutros, Stella; Sørensen, Karina Dalsgaard; Cybulski, Cezary; Grindedal, Eli Marie; Menegaux, Florence; Park, Jong; Ingles, Sue; Maier, Christiane; Hamilton, Robert; Rosenstein, Barry; Lu, Yong-Jie; Watya, Stephen; Vega, Ana; Kogevinas, Manolis; Wiklund, Fredrik; Penney, Kathryn; Huff, Chad; Teixeira, Manuel; Multigner, Luc; Leach, Robin; Brenner, Hermann; John, Esther; Kaneva, Radka; Logothetis, Christopher; Neuhausen, Susan; De Ruyck, Kim; Ost, Piet; Razack, Azad; Newcomb, Lisa; Fowke, Jay; Gamulin, Marija; Abraham, Aswin; Claessens, Frank; Castelao, Jose Esteban; Townsend, Paul; Crawford, Dana; Petrovics, Gyorgy; van Schaik, Ron H.N.; Parent, Marie-Élise; Hu, Jennifer; Zheng, Wei; Mills, Ian; Andreassen, Ole; Dale, Anders; Seibert, Tyler; 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 |
| Source: |
medRxiv |
| Publication Year: |
2021 |
| Subject Terms: |
APCB (Australian Prostate Cancer BioResource); Canary PASS Investigators; NC-LA PCaP Investigators; The IMPACT Study Steering Committee and Collaborators; The PRACTICAL Consortium; The Profile Study Steering Committee; UKGPCS collaborators |
| Description: |
Introduction Prostate 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. Methods In 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. Results The 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. Conclusion We 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 ... |
| Document Type: |
report |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
https://lirias.kuleuven.be/handle/123456789/684888; https://doi.org/10.1101/2021.08.14.21261931 |
| DOI: |
10.1101/2021.08.14.21261931 |
| Availability: |
https://lirias.kuleuven.be/handle/123456789/684888; https://lirias.kuleuven.be/retrieve/eab7c1f6-d989-402c-a9f4-cf0b775da56d; https://doi.org/10.1101/2021.08.14.21261931 |
| Rights: |
info:eu-repo/semantics/openAccess ; public ; All rights reserved |
| Accession Number: |
edsbas.12E82B78 |
| Database: |
BASE |