Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry

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

doi:10.1016/j.ebiom.2019.09.006

Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry

EBioMedicine. 2019 Oct:48:203-211. doi: 10.1016/j.ebiom.2019.09.006. Epub 2019 Oct 16.

Authors

Yaohua Yang¹, Xiang Shu¹, Xiao-Ou Shu¹, Manjeet K Bolla², Sun-Seog Kweon³, Qiuyin Cai¹, Kyriaki Michailidou², Qin Wang², Joe Dennis², Boyoung Park⁴, Keitaro Matsuo⁵, Ava Kwong⁶, Sue Kyung Park⁷, Anna H Wu⁸, Soo Hwang Teo⁹, Motoki Iwasaki¹⁰, Ji-Yeob Choi¹¹, Jingmei Li¹², Mikael Hartman¹³, Chen-Yang Shen¹⁴, Kenneth Muir¹⁵, Artitaya Lophatananon¹⁵, Bingshan Li¹⁶, Wanqing Wen¹, Yu-Tang Gao¹⁷, Yong-Bing Xiang¹⁸, Kristan J Aronson¹⁹, John J Spinell²⁰, Manuela Gago-Dominguez²¹, Esther M John²², Allison W Kurian²³, Jenny Chang-Claude²⁴, Shou-Tung Chen²⁵, Thilo Dörk²⁶, D Gareth R Evans²⁷, Marjanka K Schmidt²⁸, Min-Ho Shin³, Graham G Giles²⁹, Roger L Milne³⁰, Jacques Simard³¹, Michiaki Kubo³², Peter Kraft³³, Daehee Kang⁷, Douglas F Easton², Wei Zheng¹, Jirong Long³⁴

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
³ Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea.
⁴ Department of Medicine, College of Medicine, Hanyang University, Seoul, South Korea.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁹ Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia; Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
¹⁰ Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
¹¹ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea.
¹² Human Genetics, Genome Institute of Singapore, Singapore; Department of Surgery, National University Hospital, Singapore.
¹³ Department of Surgery, National University Hospital, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
¹⁴ School of Public Health, China Medical University, Taichung, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
¹⁵ Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK; Institute of Population Health, University of Manchester, Manchester, UK.
¹⁶ Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
¹⁷ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
¹⁸ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁹ Department of Public Health Sciences, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
²⁰ Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
²¹ 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.
²² 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.
²³ 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.
²⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁵ Division of General Surgery, Changhua Christian Hospital, Changhua, Taiwan.
²⁶ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²⁷ Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK; Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
²⁸ 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.
²⁹ 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.
³⁰ 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.
³¹ Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Quebec, Canada.
³² RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³³ 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.
³⁴ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: jirong.long@vanderbilt.edu.

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: Breast cancer risk; Candidate gene studies; Genetic variants; Re-evaluation.

MeSH terms

Alleles
Asian People* / genetics
Breast Neoplasms / epidemiology*
Breast Neoplasms / genetics*
Caspase 8
Female
Genetic Predisposition to Disease*
Genetic Variation*
Genotype
Humans
Odds Ratio
Polymorphism, Single Nucleotide
Population Surveillance
Risk
White People* / genetics

Substances

CASP8 protein, human
Caspase 8

Abstract

MeSH terms

Substances

Grants and funding