Title

Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Authors

Minh-Phuong Huynh-Le, Radiation Oncology, George Washington University, Washington, DC, USA.
Roshan Karunamuni, Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.
Chun Chieh Fan, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
Lui Asona, Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.
Wesley K. Thompson, Division of Biostatistics and Halicioğlu Data Science Institute, University of California San Diego, La Jolla, CA, USA.
Maria Elena Martinez, University of California San Diego, Moores Cancer Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, 92093-0012, USA.
Rosalind A. Eeles, The Institute of Cancer Research, London, SM2 5NG, UK.
Zsofia Kote-Jarai, The Institute of Cancer Research, London, SM2 5NG, UK.
Kenneth R. Muir, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Artitaya Lophatananon, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Johanna Schleutker, Institute of Biomedicine, University of Turku, Turku, Finland.
Nora Pashayan, Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
Jyotsna Batra, Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
Henrik Grönberg, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden.
David E. Neal, Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK.
Børge G. Nordestgaard, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
Catherine M. Tangen, SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Robert J. MacInnis, Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.
Alicja Wolk, Department of Surgical Sciences, Uppsala University, 75185, Uppsala, Sweden.
Demetrius Albanes, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Christopher A. Haiman, Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
Ruth C. Travis, Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
William J. Blot, Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, 37232, USA.
Janet L. Stanford, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
Lorelei A. Mucci, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
Catharine M. West, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, M13 9PL, UK.
Sune F. Nielsen, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
Adam S. Kibel, Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA, 02115, USA.
Olivier Cussenot, Sorbonne Universite, GRC n°5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-45020, Paris, France.
Sonja I. Berndt, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Stella Koutros, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Karina Dalsgaard Sørensen, Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200, Aarhus N, Denmark.

Document Type

Journal Article

Publication Date

2-12-2022

Journal

Prostate cancer and prostatic diseases

DOI

10.1038/s41391-022-00497-7

Abstract

BACKGROUND: 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 of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: 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 approaches to prostate cancer screening decisions in diverse populations.

Department

Radiology

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