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Polygenic risk scores for prediction of breast cancer risk in Asian populations

Ho WK 1 , Tai MC 2 , Dennis J 3 , Shu X 4 , Li J 5 , Ho PJ 6 Show all authors , Millwood IY 7 , Lin K 8 , Jee YH 9 , Lee SH 10 , Mavaddat N 3 , Bolla MK 3 , Wang Q 3 , Michailidou K 11 , Long J 12 , Wijaya EA 2 , Hassan T 2 , Rahmat K 13 , Tan VKM 14 , Tan BKT 15 , Tan SM 16 , Tan EY 17 , Lim SH 18 , Gao YT 19 , Zheng Y 20 , Kang D 21 , Choi JY 22 , Han W 23 , Lee HB 23 , Kubo M 24 , Okada Y 25 , Namba S 26 , BioBank Japan Project 27 , Park SK 28 , Kim SW 29 , Shen CY 30 , Wu PE 30 , Park B 31 , Muir KR 32 , Lophatananon A 32 , Wu AH 33 , Tseng CC 33 , Matsuo K 34 , Ito H 35 , Kwong A 36 , Chan TL 37 , John EM 38 , Kurian AW 38 , Iwasaki M 39 , Yamaji T 39 , Kweon SS 40 , Aronson KJ 41 , Murphy RA 42 , Koh WP 43 , Khor CC 44 , Yuan JM 45 , Dorajoo R 46 , Walters RG 7 , Chen Z 7 , Li L 47 , Lv J 47 , Jung KJ 48 , Kraft P 49 , Pharoah PDB 50 , Dunning AM 51 , Simard J 52 , Shu XO 12 , Yip CH 53 , Taib NAM 54 , Antoniou AC 3 , Zheng W 12 , Hartman M 55 , Easton DF 50 , Teo SH 56

Affiliations 

  • 1 School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Selangor, Malaysia; Cancer Research Malaysia, Selangor, Malaysia. Electronic address: [email protected]
  • 2 Cancer Research Malaysia, Selangor, Malaysia
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 4 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN; Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
  • 5 Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore; Genome Institute of Singapore, Laboratory of Women's Health and Genetics, Singapore, Singapore
  • 6 Genome Institute of Singapore, Laboratory of Women's Health and Genetics, Singapore, Singapore
  • 7 Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; MRC Population Health Research Unit, University of Oxford, Oxford, United Kingdom
  • 8 Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 9 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
  • 10 Graduate School of Public Health, Yonsei University, Seoul, Korea
  • 11 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Ayios Dometios, Cyprus; Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Ayios Dometios, Cyprus
  • 12 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN
  • 13 Biomedical Imaging Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 14 Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore; Division of Surgery and Surgical Oncology, National Cancer Center Singapore, Singapore, Singapore
  • 15 Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore; Division of Surgery and Surgical Oncology, National Cancer Center Singapore, Singapore, Singapore; Department of General Surgery, Sengkang General Hospital, Singapore, Singapore
  • 16 Division of Breast Surgery, Changi General Hospital, Singapore, Singapore
  • 17 Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
  • 18 KK Breast Department, KK Women's and Children's Hospital, Singapore, Singapore
  • 19 State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  • 20 Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
  • 21 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea
  • 22 Cancer Research Institute, Seoul National University, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Institute of Health Policy and Management, Medical Research Center, Seoul National University, Seoul, Korea
  • 23 Cancer Research Institute, Seoul National University, Seoul, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
  • 24 RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
  • 25 Department of Statistical Genetics, Graduate School of Medicine, Faculty of Medicine, Osaka University, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
  • 26 Department of Statistical Genetics, Graduate School of Medicine, Faculty of Medicine, Osaka University, Suita, Japan
  • 27 Institute of Medical Science, The University of Tokyo, Tokyo, Japan
  • 28 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea; Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Korea
  • 29 Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea
  • 30 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 31 Department of Medicine, Hanyang University College of Medicine, Seoul, Korea
  • 32 Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, The University of Manchester, Manchester, United Kingdom
  • 33 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
  • 34 Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  • 35 Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan; Division of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Japan
  • 36 Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong; Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong; Department of Surgery, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong
  • 37 Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong; Department of Pathology, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong
  • 38 Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA; Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA
  • 39 Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
  • 40 Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea
  • 41 Department of Public Health Sciences, and Cancer Research Institute, School of Medicine, Queen's University, Kingston, Ontario, Canada
  • 42 Cancer Control Research, BC Cancer, Vancouver, British Columbia, Canada; School of Population and Public Health, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
  • 43 Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
  • 44 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
  • 45 Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
  • 46 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
  • 47 Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
  • 48 Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea
  • 49 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
  • 50 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 51 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 52 Genomics Center, CHU de Québec-Université Laval Research Center, Quebec City, Quebec, Canada
  • 53 Subang Jaya Medical Centre, Selangor, Malaysia
  • 54 Department of Surgery, Faculty of Medicine, University of Malaya Centre, UM Cancer Research Institute, Kuala Lumpur, Malaysia
  • 55 Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
  • 56 Cancer Research Malaysia, Selangor, Malaysia; Department of Surgery, Faculty of Medicine, University of Malaya Centre, UM Cancer Research Institute, Kuala Lumpur, Malaysia. Electronic address: [email protected]
Genet Med, 2022 Mar;24(3):586-600.
PMID: 34906514 DOI: 10.1016/j.gim.2021.11.008

Abstract

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups.

METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases).

RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk.

CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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