Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Jiajun Shi; Yanfeng Zhang; Wei Zheng; Kyriaki Michailidou; Maya Ghoussaini; Manjeet K Bolla; Qin Wang; Joe Dennis; Michael Lush; Roger L Milne; Xiao-Ou Shu; Jonathan Beesley; Siddhartha Kar; Irene L Andrulis; Hoda Anton-Culver; Volker Arndt; Matthias W Beckmann; Zhiguo Zhao; Xingyi Guo; Javier Benitez; Alicia Beeghly-Fadiel; William Blot; Natalia V Bogdanova; Stig E Bojesen; Hiltrud Brauch; Hermann Brenner; Louise Brinton; Annegien Broeks; Thomas Brüning; Barbara Burwinkel; Hui Cai; Sander Canisius; Jenny Chang-Claude; Ji-Yeob Choi; Fergus J Couch; Angela Cox; Simon S Cross; Kamila Czene; Hatef Darabi; Peter Devilee; Arnaud Droit; Thilo Dork; Peter A Fasching; Olivia Fletcher; Henrik Flyger; Florentia Fostira; Valerie Gaborieau; Montserrat García-Closas; Graham G Giles; Mervi Grip; Pascal Guenel; Christopher A Haiman; Ute Hamann; Mikael Hartman; Hui Miao; Antoinette Hollestelle; John L Hopper; Chia-Ni Hsiung; kConFab Investigators; Hidemi Ito; Anna Jakubowska; Nichola Johnson; Diana Torres; Maria Kabisch; Daehee Kang; Sofia Khan; Julia A Knight; Veli-Matti Kosma; Diether Lambrechts; Jingmei Li; Annika Lindblom; Artitaya Lophatananon; Jan Lubinski; Arto Mannermaa; Siranoush Manoukian; Loic Le Marchand; Sara Margolin; Frederik Marme; Keitaro Matsuo; Catriona McLean; Alfons Meindl; Kenneth Muir; Susan L Neuhausen; Heli Nevanlinna; Silje Nord; Anne-Lise Børresen-Dale; Janet E Olson; Nick Orr; Ans M W van den Ouweland; Paolo Peterlongo; Thomas Choudary Putti; Anja Rudolph; Suleeporn Sangrajrang; Elinor J Sawyer; Marjanka K Schmidt; Rita K Schmutzler; Chen-Yang Shen; Ming-Feng Hou; Matha J Shrubsole; Melissa C Southey; Anthony Swerdlow; Soo Hwang Teo; Bernard Thienpont; Amanda E Toland; Robert A E M Tollenaar; Ian Tomlinson; Therese Truong; Chiu-Chen Tseng; Wanqing Wen; Robert Winqvist; Anna H Wu; Cheng Har Yip; Pilar M Zamora; Ying Zheng; Giuseppe Floris; Ching-Yu Cheng; Maartje J Hooning; John W M Martens; Caroline Seynaeve; Vessela N Kristensen; Per Hall; Paul D P Pharoah; Jacques Simard; Georgia Chenevix-Trench; Alison M Dunning; Antonis C Antoniou; Douglas F Easton; Qiuyin Cai; Jirong Long

doi:10.1002/ijc.30150

Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Int J Cancer. 2016 Sep 15;139(6):1303-1317. doi: 10.1002/ijc.30150. Epub 2016 Jun 17.

Authors

Jiajun Shi^#¹, Yanfeng Zhang^#¹, Wei Zheng¹, Kyriaki Michailidou², Maya Ghoussaini³, Manjeet K Bolla², Qin Wang², Joe Dennis³, Michael Lush³, Roger L Milne^{4

5}, Xiao-Ou Shu¹, Jonathan Beesley⁶, Siddhartha Kar³, Irene L Andrulis^{7

8}, Hoda Anton-Culver⁹, Volker Arndt¹⁰, Matthias W Beckmann¹¹, Zhiguo Zhao¹, Xingyi Guo¹, Javier Benitez^{12

13}, Alicia Beeghly-Fadiel¹, William Blot^{1

14}, Natalia V Bogdanova¹⁵, Stig E Bojesen^{16

17

18}, Hiltrud Brauch^{19

20

21}, Hermann Brenner^{10

21

22}, Louise Brinton²³, Annegien Broeks²⁴, Thomas Brüning²⁵, Barbara Burwinkel^{26

27}, Hui Cai¹, Sander Canisius²⁸, Jenny Chang-Claude²⁹, Ji-Yeob Choi^{30

31}, Fergus J Couch³², Angela Cox³³, Simon S Cross³⁴, Kamila Czene³⁵, Hatef Darabi³⁵, Peter Devilee^{36

37}, Arnaud Droit³⁸, Thilo Dork³⁹, Peter A Fasching^{11

40}, Olivia Fletcher⁴¹, Henrik Flyger⁴², Florentia Fostira⁴³, Valerie Gaborieau⁴⁴, Montserrat García-Closas^{41

45}, Graham G Giles^{4

5}; Mervi Grip; Pascal Guenel^{46

47}, Christopher A Haiman⁴⁸, Ute Hamann⁴⁹, Mikael Hartman^{50

51}, Hui Miao⁵⁰, Antoinette Hollestelle⁵², John L Hopper⁵³, Chia-Ni Hsiung⁵⁴; kConFab Investigators; Hidemi Ito⁵⁵, Anna Jakubowska⁵⁶, Nichola Johnson⁴¹, Diana Torres^{49

57}, Maria Kabisch⁴⁹, Daehee Kang^{30

31

58}, Sofia Khan⁵⁸, Julia A Knight^{59

60}, Veli-Matti Kosma^{61

62}, Diether Lambrechts^{63

64}, Jingmei Li³⁵, Annika Lindblom⁶⁵, Artitaya Lophatananon⁶⁶, Jan Lubinski⁵⁶, Arto Mannermaa^{61

62}, Siranoush Manoukian⁶⁷, Loic Le Marchand⁶⁸, Sara Margolin⁶⁹, Frederik Marme^{70

71}, Keitaro Matsuo⁷², Catriona McLean⁷³, Alfons Meindl⁵³, Kenneth Muir^{66

74}, Susan L Neuhausen⁷⁵, Heli Nevanlinna⁵⁸, Silje Nord^{76

77}, Anne-Lise Børresen-Dale^{76

77}, Janet E Olson⁷⁸, Nick Orr⁷⁹, Ans M W van den Ouweland⁸⁰, Paolo Peterlongo⁸¹, Thomas Choudary Putti⁸², Anja Rudolph²⁹, Suleeporn Sangrajrang⁸³, Elinor J Sawyer⁸⁴, Marjanka K Schmidt²⁴, Rita K Schmutzler^{85

86

87

88}, Chen-Yang Shen^{89

90}, Ming-Feng Hou⁹¹, Matha J Shrubsole¹, Melissa C Southey⁹², Anthony Swerdlow⁹³, Soo Hwang Teo^{94

95}, Bernard Thienpont^{63

64}, Amanda E Toland⁹⁶, Robert A E M Tollenaar⁹⁷, Ian Tomlinson⁹⁸, Therese Truong^{46

47}, Chiu-Chen Tseng⁴⁸, Wanqing Wen¹, Robert Winqvist^{99

100}, Anna H Wu⁴⁸, Cheng Har Yip⁹⁵, Pilar M Zamora¹⁰¹, Ying Zheng¹⁰², Giuseppe Floris¹⁰³, Ching-Yu Cheng¹⁰⁴, Maartje J Hooning⁵², John W M Martens⁵², Caroline Seynaeve⁵², Vessela N Kristensen^{76

77

105}, Per Hall³⁵, Paul D P Pharoah^{2

3}, Jacques Simard³⁸, Georgia Chenevix-Trench^{6

106}, Alison M Dunning³, Antonis C Antoniou², Douglas F Easton^{2

3}, Qiuyin Cai¹, Jirong Long¹

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
⁴ Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria 3053, Australia.
⁵ Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Victoria 3053, Australia.
⁶ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁷ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁹ Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA.
¹⁰ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg 69120, Germany.
¹¹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen 91054, Germany.
¹² Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid 28029, Spain.
¹³ Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
¹⁴ International Epidemiology Institute, Rockville, MD 20850, USA.
¹⁵ Department of Radiation Oncology, Hannover Medical School, Hannover 30625, Germany.
¹⁶ Copenhagen General Population Study, Herlev Hospital, 2730 Herlev, Denmark.
¹⁷ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
¹⁸ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart 70376, Germany.
²⁰ University of Tübingen, Tübingen 72074, Germany.
²¹ German Cancer Consortium, German Cancer Research Center(DKFZ), Heidelberg 69120, Germany.
²² Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
²³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.
²⁴ Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam 1066 CX, The Netherlands.
²⁵ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Bochum 44789, Germany.
²⁶ Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg 69120, Germany.
²⁷ Molecular Epidemiology Group, German Cancer Research Center, Heidelberg 69120, Germany.
²⁸ Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands.
²⁹ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg 69120, Germany.
³⁰ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea.
³¹ Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
³² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
³³ Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK.
³⁴ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
³⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-17177, Sweden.
³⁶ Separtment of Pathology, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands.
³⁷ Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands.
³⁸ Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City G1V 4G2, Canada.
³⁹ Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
⁴⁰ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
⁴¹ Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
⁴² Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
⁴³ Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", 153 10 Athens, Greece.
⁴⁴ International Agency for Research on Cancer, Lyon 69372, France.
⁴⁵ Division of Genetics and Epidemiology, Institute of Cancer Research, London SW7 3RP, UK.
⁴⁶ Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif 94807, France.
⁴⁷ University Paris-Sud, Villejuif 94807, France.
⁴⁸ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴⁹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁵⁰ Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore.
⁵¹ Department of Surgery, National University Health System, Singapore 117597.
⁵² Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 CN Rotterdam, The Netherlands.
⁵³ Division of Gynaecology and Obstetrics, Technische Universität München, Munich 81675, Germany.
⁵⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
⁵⁵ Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan.
⁵⁶ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland.
⁵⁷ Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota 12362, Colombi.
⁵⁸ Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, FI-00029 HUS, Finland.
⁵⁹ Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
⁶⁰ Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁶¹ School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finlan.
⁶² Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio 70210, Finland.
⁶³ Vesalius Research Center, Leuven 3000, Belgium.
⁶⁴ Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven 3000, Belgium.
⁶⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-17177, Sweden.
⁶⁶ Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
⁶⁷ Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan 20133, Italy.
⁶⁸ University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
⁶⁹ Department of Oncology - Pathology, Karolinska Institutet, Stockholm SE-17177, Sweden.
⁷⁰ National Center for Tumor Diseases, University of Heidelberg, Heidelberg 69120, Germany.
⁷¹ Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany.
⁷² Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
⁷³ Anatomical Pathology, The Alfred Hospital, Melbourne, , Victoria 3004, Australia.
⁷⁴ Institute of Population Health, University of Manchester, Manchester M13 9PL, UK.
⁷⁵ Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
⁷⁶ Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, N-0310 Oslo, Norway.
⁷⁷ K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway.
⁷⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
⁷⁹ Division of Breast Cancer Research, Institute of Cancer Research, London, UK; Cancer Research, Institute of Cancer Research, London SW3 6JB, UK.
⁸⁰ Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
⁸¹ IFOM, the FIRC Institute of Molecular Oncology, Milan 20139, Italy.
⁸² Department of Pathology, National University Health System, Singapore 117597.
⁸³ National Cancer Institute, Bangkok 10400, Thailand.
⁸⁴ Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK.
⁸⁵ Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne 50931, Germany.
⁸⁶ Center for Integrated Oncology, University Hospital of Cologne, Cologne 50931, Germany.
⁸⁷ Center for Molecular Medicine, University Hospital of Cologne, Cologne 50931, Germany.
⁸⁸ Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne 50931, Germany.
⁸⁹ School of Public Health, China Medical University, Taichung 404, Taiwan.
⁹⁰ Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
⁹¹ Cancer Center and Department of Surgery, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁹² Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
⁹³ Division of Genetics and Epidemiology and Division of Breast Cancer Research, Institute of Cancer Research, London SW7 3RP, UK.
⁹⁴ Cancer Research Initiatives Foundation, 47500 Subang Jaya, Selangor, Malaysia.
⁹⁵ Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 59100 KualaLumpur, Malaysia.
⁹⁶ Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
⁹⁷ Department of Surgical Oncology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.
⁹⁸ Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
⁹⁹ Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry, University of Oulu, Oulu FI-90220, Finland.
¹⁰⁰ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu FI-90220, Finland.
¹⁰¹ Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid 28046, Spain.
¹⁰² Shanghai Municipal Center for Disease Control and Prevention, Shanghai, 200336, PR China.
¹⁰³ University Hospital Gashuisberg, Leuven, Belgium.
¹⁰⁴ Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore.
¹⁰⁵ Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, University of Oslo (UiO), Oslo, Norway.
¹⁰⁶ Peter MacCallum Cancer Centre, The University of Melbourne, East Melbourne, VIC 3002, Australi.

^# Contributed equally.

Abstract

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Keywords: 8q24; breast cancer; fine-mapping; genetic susceptibility; single nucleotide polymorphism.

Publication types

Meta-Analysis

MeSH terms

Alleles
Breast Neoplasms / epidemiology*
Breast Neoplasms / genetics*
Case-Control Studies
Chromosome Mapping*
Chromosomes, Human, Pair 8 / genetics*
Female
Genetic Variation*
Genome-Wide Association Study
Genotype
Haplotypes
Humans
Linkage Disequilibrium
Odds Ratio
Polymorphism, Single Nucleotide
Quantitative Trait Loci*
Risk
White People / genetics

Abstract

Publication types

MeSH terms

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