Polygenic risk scores for prediction of breast cancer risk in women of African ancestry: a cross-ancestry approach

Author:

Gao Guimin1,Zhao Fangyuan1,Ahearn Thomas U2,Lunetta Kathryn L3,Troester Melissa A4,Du Zhaohui5,Ogundiran Temidayo O6,Ojengbede Oladosu7,Blot William8,Nathanson Katherine L9,Domchek Susan M9,Nemesure Barbara10,Hennis Anselm1011,Ambs Stefan12,McClellan Julian1,Nie Mark1,Bertrand Kimberly13,Zirpoli Gary13,Yao Song14,Olshan Andrew F4,Bensen Jeannette T4,Bandera Elisa V15,Nyante Sarah16,Conti David V17,Press Michael F18,Ingles Sue A17,John Esther M19,Bernstein Leslie20,Hu Jennifer J21,Deming-Halverson Sandra L8,Chanock Stephen J2,Ziegler Regina G2,Rodriguez-Gil Jorge L22,Sucheston-Campbell Lara E23,Sandler Dale P24,Taylor Jack A24,Kitahara Cari M25,O’Brien Katie M24,Bolla Manjeet K26,Dennis Joe26,Dunning Alison M27ORCID,Easton Douglas F2627,Michailidou Kyriaki28,Pharoah Paul D P2627,Wang Qin26,Figueroa Jonine2930,Biritwum Richard31,Adjei Ernest32,Wiafe Seth33,Ambrosone Christine B14,Zheng Wei8,Olopade Olufunmilayo I34,García-Closas Montserrat2,Palmer Julie R13,Haiman Christopher A17,Huo Dezheng134ORCID,

Affiliation:

1. Department of Public Health Sciences , The University of Chicago, Chicago, IL 60637 , USA

2. Division of Cancer Epidemiology and Genetics , National Cancer Institute, National Institutes of Health, Bethesda, MD 20850 , USA

3. Department of Biostatistics , Boston University School of Public Health, Boston, MA 02118 , USA

4. Department of Epidemiology , Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 , USA

5. Public Health Sciences Division , Fred Hutchinson Cancer Research Center, Seattle, WA 98109 , USA

6. Department of Surgery , College of Medicine, University of Ibadan, Ibadan, Nigeria

7. Centre for Population & Reproductive Health , College of Medicine, University of Ibadan, Ibadan, Nigeria

8. Division of Epidemiology , Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232 , USA

9. Department of Medicine , Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 , USA

10. Department of Family , Population and Preventive Medicine, Stony Brook University, Stony Brook, NY 11794, USA

11. University of the West Indies , Bridgetown, Bardados

12. Laboratory of Human Carcinogenesis , National Cancer Institute, Bethesda, MD 20892 , USA

13. Slone Epidemiology Center , Boston University, Boston, MA 02215 , USA

14. Department of Cancer Prevention and Control , Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203 , USA

15. Cancer Prevention and Control Program , Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903 , USA

16. Department of Radiology , School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 , USA

17. Department of Preventive Medicine , Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 , USA

18. Department of Pathology , Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 , USA

19. Departments of Epidemiology & Population Health and of Medicine (Oncology) and Stanford Cancer Institute , Stanford University School of Medicine, Stanford, CA 94304 , USA

20. Biomarkers of Early Detection and Prevention , Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010 , USA

21. Department of Public Health Sciences , University of Miami Miller School of Medicine, Miami, FL 33136 , USA

22. Genomics , Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20894 , USA

23. Department of Veterinary Biosciences , College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210 , USA

24. Epidemiology Branch , National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709 , USA

25. Radiation Epidemiology Branch , Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 , USA

26. Department of Public Health and Primary Care , Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN , UK

27. Department of Oncology , Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN , UK

28. Biostatistics Unit , The Cyprus Institute of Neurology & Genetics, Nicosia 2371 , Cyprus

29. Usher Institute of Population Health Sciences and Informatics , The University of Edinburgh Medical School, Edinburgh EH16 5TJ , UK

30. Cancer Research UK Edinburgh Centre , Edinburgh EH4 2XR , UK

31. University of Ghana , Accra, Ghana

32. Komfo Anokye Teaching Hospital , Kumasi, Ghana

33. School of Public Health , Loma Linda University, Loma Linda, CA 92350 , USA

34. Center for Clinical Cancer Genetics & Global Health , The University of Chicago, Chicago, IL 60637 , USA

Abstract

Abstract Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27–1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th–60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63–2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.

Funder

Norris Foundation

Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH

Susan G. Komen Foundation

Breast Cancer Research Foundation

National Cancer Institute

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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