Testing the generalizability of ancestry-specific polygenic risk scores to predict prostate cancer in sub-Saharan Africa.

Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa.

Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608-0.707, OR 2.37-5.71) than for African individuals (AUC 0.502-0.585, OR 0.95-2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores.

Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.

Genome biology. 2022 Sep 13*** epublish ***

Michelle S Kim, Daphne Naidoo, Ujani Hazra, Melanie H Quiver, Wenlong C Chen, Corinne N Simonti, Paidamoyo Kachambwa, Maxine Harlemon, Ilir Agalliu, Shakuntala Baichoo, Pedro Fernandez, Ann W Hsing, Mohamed Jalloh, Serigne M Gueye, Lamine Niang, Halimatou Diop, Medina Ndoye, Nana Yaa Snyper, Ben Adusei, James E Mensah, Afua O D Abrahams, Richard Biritwum, Andrew A Adjei, Akindele O Adebiyi, Olayiwola Shittu, Olufemi Ogunbiyi, Sikiru Adebayo, Oseremen I Aisuodionoe-Shadrach, Maxwell M Nwegbu, Hafees O Ajibola, Olabode P Oluwole, Mustapha A Jamda, Elvira Singh, Audrey Pentz, Maureen Joffe, Burcu F Darst, David V Conti, Christopher A Haiman, Petrus V Spies, André van der Merwe, Thomas E Rohan, Judith Jacobson, Alfred I Neugut, Jo McBride, Caroline Andrews, Lindsay N Petersen, Timothy R Rebbeck, Joseph Lachance

School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Dr, Atlanta, GA, 30332, USA., Centre for Proteomic and Genomic Research, Cape Town, South Africa., Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA., University of Mauritius, RĂ©duit, Mauritius., Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa., Stanford Cancer Institute, Stanford University, Stanford, CA, USA., Universite Cheikh Anta Diop de Dakar, Dakar, Senegal., 37 Military Hospital, Accra, Ghana., Korle-Bu Teaching Hospital and University of Ghana Medical School, Accra, Ghana., Department of Pathology, University of Ghana Medical School, Accra, Ghana., College of Medicine, University of Ibadan, Ibadan, Nigeria., College of Health Sciences, University of Abuja and University of Abuja Teaching Hospital, Abuja, Nigeria., National Cancer Registry, National Health Laboratory Service, Johannesburg, South Africa., Non-Communicable Diseases Research Division, Wits Health Consortium (PTY) Ltd, Johannesburg, South Africa., Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA., Dana-Farber Cancer Institute, Boston, MA, USA., School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Dr, Atlanta, GA, 30332, USA. .

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