Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: a meta-analysis within diverse populations

  1. Fei Chen
  2. Burcu F Darst
  3. Ravi K Madduri
  4. Alex A Rodriguez
  5. Xin Sheng
  6. Christopher T Rentsch
  7. Caroline Andrews
  8. Wei Tang
  9. Adam S Kibel
  10. Anna Plym
  11. Kelly Cho
  12. Mohamed Jalloh
  13. Serigne Magueye Gueye
  14. Lamine Niang
  15. Olufemi J Ogunbiyi
  16. Olufemi Popoola
  17. Akindele O Adebiyi
  18. Oseremen I Aisuodionoe-Shadrach
  19. Hafees O Ajibola
  20. Mustapha A Jamda
  21. Olabode P Oluwole
  22. Maxwell Nwegbu
  23. Ben Adusei
  24. Sunny Mante
  25. Afua Darkwa-Abrahams
  26. James E Mensah
  27. Andrew Anthony Adjei
  28. Halimatou Diop
  29. Joseph Lachance
  30. Timothy R Rebbeck
  31. Stefan Ambs
  32. J Michael Gaziano
  33. Amy C Justice
  34. David V Conti
  35. Christopher A Haiman  Is a corresponding author
  1. University of Southern California, United States
  2. Fred Hutchinson Cancer Research Center, United States
  3. Argonne National Laboratory, United States
  4. Yale School of Medicine, United States
  5. Dana-Farber Cancer Institute, United States
  6. National Institutes of Health, United States
  7. Brigham and Women's Hospital, United States
  8. Harvard TH Chan School of Public Health, United States
  9. VA Boston Healthcare System, United States
  10. Hôpital Général Idrissa Pouye, Senegal
  11. University of Ibadan, Nigeria
  12. University of Abuja Teaching Hospital, Nigeria
  13. 37 Military Hospital, Ghana
  14. Korle-Bu Teaching Hospital, Ghana
  15. Hôpital Aristide Le Dantec, Senegal
  16. Georgia Institute of Technology, United States
  17. VA Connecticut Healthcare System, United States
  18. University of Southern California, Spain

Abstract

Background: We recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program (MVP) and additional independent studies.

Methods: Within each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case-control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population.

Results: The PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8,794 cases, 55,657 controls), and Hispanic (1,082 cases, 20,601 controls) populations. Comparing men in the top decile (90-100% of the PRS) to the average 40-60% PRS category, the prostate cancer odds ratio (OR) was 3.8-fold in European ancestry men (95% CI=3.62-3.96), 2.8-fold in African ancestry men (95% CI=2.59-3.03), and 3.2-fold in Hispanic men (95% CI=2.64-3.92). The PRS did not discriminate risk of aggressive versus non-aggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: ≤55 years, OR=7.11; 55-60 years, OR=4.26; >70 years, OR=2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk ~10 years younger than men in the 40-60% PRS category.

Conclusions: Our findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine if the PRS could be used for risk-stratified screening and early detection.

Funding: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Data availability

This investigation included published results from the following studies under DOI numbers 10.1038/s41588-020-00748-0 and 10.1093/jnci/djab058. For the MVP data, the final data sets underlying this study cannot be shared outside the VA, except as required under the Freedom of Information Act (FOIA), per VA policy. However, upon request through the formal mechanisms in place and pending approval from the VHA Office of Research Oversight (ORO), a de-identified, anonymized dataset underlying this study can be created. Upon request through the formal mechanisms provided by the VHA ORO, we would be able to provide sufficiently detailed variable names and definitions to allow replication of our work. Any requests for data access should be directed to the VHA ORO (OROCROW@va.gov), and should reference the following project and analysis: 'MVP017: A VA-DOE Exemplar Project on Cancer'. Publicly available data described in this manuscript can be found from the following websites: 1000 Genomes Project (https://www.internationalgenome.org/); SEER (https://seer.cancer.gov/); National Center for Health Statistics, and CDC (https://www.cdc.gov/nchs/index.htm).

Article and author information

Author details

  1. Fei Chen

    Department of Population and Public Health Sciences, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1679-9932
  2. Burcu F Darst

    Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    Burcu F Darst, received honorarium for presentations at Society of Urology Oncology Annual Meeting (2021) and the Social Genomics Group at the University of Wisconsin, Madison (2021). The author has no other competing interests to declare..
  3. Ravi K Madduri

    Argonne National Laboratory, Lemont, United States
    Competing interests
    Ravi K Madduri, has stock or stock options in Navipoint Genomics LLC. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2130-2887
  4. Alex A Rodriguez

    Argonne National Laboratory, Lemont, United States
    Competing interests
    No competing interests declared.
  5. Xin Sheng

    Department of Population and Public Health Sciences, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  6. Christopher T Rentsch

    Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  7. Caroline Andrews

    Harvard TH Chan School of Public Health and Division of Population Sciences, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  8. Wei Tang

    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  9. Adam S Kibel

    Department of Surgery, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  10. Anna Plym

    Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.
  11. Kelly Cho

    VA Boston Healthcare System, Boston, United States
    Competing interests
    No competing interests declared.
  12. Mohamed Jalloh

    Hôpital Général Idrissa Pouye, Dakar, Senegal
    Competing interests
    No competing interests declared.
  13. Serigne Magueye Gueye

    Hôpital Général Idrissa Pouye, Dakar, Senegal
    Competing interests
    No competing interests declared.
  14. Lamine Niang

    Hôpital Général Idrissa Pouye, Dakar, Senegal
    Competing interests
    No competing interests declared.
  15. Olufemi J Ogunbiyi

    College of Medicine, University of Ibadan, Ibadan, Nigeria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8748-2879
  16. Olufemi Popoola

    College of Medicine, University of Ibadan, Ibadan, Nigeria
    Competing interests
    No competing interests declared.
  17. Akindele O Adebiyi

    College of Medicine, University of Ibadan, Ibadan, Nigeria
    Competing interests
    No competing interests declared.
  18. Oseremen I Aisuodionoe-Shadrach

    College of Health Sciences, University of Abuja Teaching Hospital, Abuja, Nigeria
    Competing interests
    No competing interests declared.
  19. Hafees O Ajibola

    College of Health Sciences, University of Abuja Teaching Hospital, Abuja, Nigeria
    Competing interests
    No competing interests declared.
  20. Mustapha A Jamda

    College of Health Sciences, University of Abuja Teaching Hospital, Abuja, Nigeria
    Competing interests
    No competing interests declared.
  21. Olabode P Oluwole

    College of Health Sciences, University of Abuja Teaching Hospital, Abuja, Nigeria
    Competing interests
    No competing interests declared.
  22. Maxwell Nwegbu

    College of Health Sciences, University of Abuja Teaching Hospital, Abuja, Nigeria
    Competing interests
    No competing interests declared.
  23. Ben Adusei

    37 Military Hospital, Accra, Ghana
    Competing interests
    No competing interests declared.
  24. Sunny Mante

    37 Military Hospital, Accra, Ghana
    Competing interests
    No competing interests declared.
  25. Afua Darkwa-Abrahams

    Korle-Bu Teaching Hospital, Accra, Ghana
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0649-3996
  26. James E Mensah

    Korle-Bu Teaching Hospital, Accra, Ghana
    Competing interests
    No competing interests declared.
  27. Andrew Anthony Adjei

    Korle-Bu Teaching Hospital, Accra, Ghana
    Competing interests
    No competing interests declared.
  28. Halimatou Diop

    Laboratoires Bacteriologie et Virologie, Hôpital Aristide Le Dantec, Dakar, Senegal
    Competing interests
    No competing interests declared.
  29. Joseph Lachance

    School of Biological Sciences, Georgia Institute of Technology, Atlanta, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4650-3741
  30. Timothy R Rebbeck

    Harvard TH Chan School of Public Health, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  31. Stefan Ambs

    Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  32. J Michael Gaziano

    Division of Aging, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  33. Amy C Justice

    VA Connecticut Healthcare System, New Haven, United States
    Competing interests
    No competing interests declared.
  34. David V Conti

    Department of Population and Public Health Sciences, University of Southern California, Los Angeles, Spain
    Competing interests
    No competing interests declared.
  35. Christopher A Haiman

    Department of Population and Public Health Sciences, University of Southern California, Los Angeles, United States
    For correspondence
    haiman@usc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0097-9971

Funding

National Cancer Institute (U19 CA214253)

  • Christopher A Haiman

Million Veteran Program (MVP017)

  • J Michael Gaziano
  • Amy C Justice

National Cancer Institute (U01 CA257328)

  • Christopher A Haiman

National Cancer Institute (U19 CA148537)

  • Christopher A Haiman

National Cancer Institute (R01 CA165862)

  • Christopher A Haiman

National Cancer Institute (K99 CA246063)

  • Burcu F Darst

National Cancer Institute (T32CA229110)

  • Fei Chen

Prostate Cancer Foundation (20CHAS03)

  • Christopher A Haiman

Prostate Cancer Foundation (21YOUN11)

  • Burcu F Darst

Achievement Rewards for College Scientists Foundation

  • Burcu F Darst

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: All study protocols were approved by each site's Institutional Review Board, and informedconsent was obtained from all study participants in accordance with the principles outlined in theDeclaration of Helsinki.

Reviewing Editor

  1. C Daniela Robles-Espinoza, International Laboratory for Human Genome Research, Mexico

Version history

  1. Received: March 1, 2022
  2. Preprint posted: May 3, 2022 (view preprint)
  3. Accepted: July 7, 2022
  4. Accepted Manuscript published: July 8, 2022 (version 1)
  5. Version of Record published: July 26, 2022 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Fei Chen
  2. Burcu F Darst
  3. Ravi K Madduri
  4. Alex A Rodriguez
  5. Xin Sheng
  6. Christopher T Rentsch
  7. Caroline Andrews
  8. Wei Tang
  9. Adam S Kibel
  10. Anna Plym
  11. Kelly Cho
  12. Mohamed Jalloh
  13. Serigne Magueye Gueye
  14. Lamine Niang
  15. Olufemi J Ogunbiyi
  16. Olufemi Popoola
  17. Akindele O Adebiyi
  18. Oseremen I Aisuodionoe-Shadrach
  19. Hafees O Ajibola
  20. Mustapha A Jamda
  21. Olabode P Oluwole
  22. Maxwell Nwegbu
  23. Ben Adusei
  24. Sunny Mante
  25. Afua Darkwa-Abrahams
  26. James E Mensah
  27. Andrew Anthony Adjei
  28. Halimatou Diop
  29. Joseph Lachance
  30. Timothy R Rebbeck
  31. Stefan Ambs
  32. J Michael Gaziano
  33. Amy C Justice
  34. David V Conti
  35. Christopher A Haiman
(2022)
Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: a meta-analysis within diverse populations
eLife 11:e78304.
https://doi.org/10.7554/eLife.78304

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https://doi.org/10.7554/eLife.78304

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