EBioMedicine (Oct 2019)
Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestryResearch in context
- Yaohua Yang,
- Xiang Shu,
- Xiao-ou Shu,
- Manjeet K. Bolla,
- Sun-Seog Kweon,
- Qiuyin Cai,
- Kyriaki Michailidou,
- Qin Wang,
- Joe Dennis,
- Boyoung Park,
- Keitaro Matsuo,
- Ava Kwong,
- Sue Kyung Park,
- Anna H. Wu,
- Soo Hwang Teo,
- Motoki Iwasaki,
- Ji-Yeob Choi,
- Jingmei Li,
- Mikael Hartman,
- Chen-Yang Shen,
- Kenneth Muir,
- Artitaya Lophatananon,
- Bingshan Li,
- Wanqing Wen,
- Yu-Tang Gao,
- Yong-Bing Xiang,
- Kristan J. Aronson,
- John J. Spinell,
- Manuela Gago-Dominguez,
- Esther M. John,
- Allison W. Kurian,
- Jenny Chang-Claude,
- Shou-Tung Chen,
- Thilo Dörk,
- D. Gareth R. Evans,
- Marjanka K. Schmidt,
- Min-Ho Shin,
- Graham G. Giles,
- Roger L. Milne,
- Jacques Simard,
- Michiaki Kubo,
- Peter Kraft,
- Daehee Kang,
- Douglas F. Easton,
- Wei Zheng,
- Jirong Long
Affiliations
- Yaohua Yang
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Xiang Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Xiao-ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Manjeet K. Bolla
- Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea
- Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Kyriaki Michailidou
- Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Qin Wang
- Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Joe Dennis
- Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Boyoung Park
- Department of Medicine, College of Medicine, Hanyang University, Seoul, South Korea
- Keitaro Matsuo
- Department of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
- Ava Kwong
- Hong Kong Hereditary Breast Cancer Family Registry, Happy Valley, Hong Kong; Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong; Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong
- Sue Kyung Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Anna H. Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Soo Hwang Teo
- Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia; Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
- Motoki Iwasaki
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
- Ji-Yeob Choi
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea
- Jingmei Li
- Human Genetics, Genome Institute of Singapore, Singapore; Department of Surgery, National University Hospital, Singapore
- Mikael Hartman
- Department of Surgery, National University Hospital, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore
- Chen-Yang Shen
- School of Public Health, China Medical University, Taichung, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- Kenneth Muir
- Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK; Institute of Population Health, University of Manchester, Manchester, UK
- Artitaya Lophatananon
- Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK; Institute of Population Health, University of Manchester, Manchester, UK
- Bingshan Li
- Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
- Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
- Yong-Bing Xiang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Kristan J. Aronson
- Department of Public Health Sciences, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada
- John J. Spinell
- Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
- Manuela Gago-Dominguez
- Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago De Compostela, Spain; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- Esther M. John
- Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
- Allison W. Kurian
- Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Shou-Tung Chen
- Division of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
- Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
- D. Gareth R. Evans
- Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK; Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK
- Marjanka K. Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Min-Ho Shin
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea
- Graham G. Giles
- Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
- Roger L. Milne
- Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
- Jacques Simard
- Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Quebec, Canada
- Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Peter Kraft
- Program in Genetic Epidemiology and Statistical Genetics, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Daehee Kang
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Douglas F. Easton
- Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Jirong Long
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Corresponding author at: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Ave, Suite 800, Nashville, TN 37203, USA.
- Journal volume & issue
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Vol. 48
pp. 203 – 211
Abstract
Background: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. Methods: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. Findings: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10−4. The associations for four variants reached P < 5 × 10−8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10−8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. Interpretation: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. Fund: National Institutes of Health. Keywords: Re-evaluation, Genetic variants, Candidate gene studies, Breast cancer risk
