Format

Send to

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

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

Shi J#1, Zhang Y#1, Zheng W1, Michailidou K2, Ghoussaini M3, Bolla MK2, Wang Q2, Dennis J3, Lush M3, Milne RL4,5, Shu XO1, Beesley J6, Kar S3, Andrulis IL7,8, Anton-Culver H9, Arndt V10, Beckmann MW11, Zhao Z1, Guo X1, Benitez J12,13, Beeghly-Fadiel A1, Blot W1,14, Bogdanova NV15, Bojesen SE16,17,18, Brauch H19,20,21, Brenner H10,21,22, Brinton L23, Broeks A24, Brüning T25, Burwinkel B26,27, Cai H1, Canisius S28, Chang-Claude J29, Choi JY30,31, Couch FJ32, Cox A33, Cross SS34, Czene K35, Darabi H35, Devilee P36,37, Droit A38, Dork T39, Fasching PA11,40, Fletcher O41, Flyger H42, Fostira F43, Gaborieau V44, García-Closas M41,45, Giles GG4,5; Mervi Grip, Guenel P46,47, Haiman CA48, Hamann U49, Hartman M50,51, Miao H50, Hollestelle A52, Hopper JL53, Hsiung CN54; kConFab Investigators, Ito H55, Jakubowska A56, Johnson N41, Torres D49,57, Kabisch M49, Kang D30,31,58, Khan S58, Knight JA59,60, Kosma VM61,62, Lambrechts D63,64, Li J35, Lindblom A65, Lophatananon A66, Lubinski J56, Mannermaa A61,62, Manoukian S67, Le Marchand L68, Margolin S69, Marme F70,71, Matsuo K72, McLean C73, Meindl A53, Muir K66,74, Neuhausen SL75, Nevanlinna H58, Nord S76,77, Børresen-Dale AL76,77, Olson JE78, Orr N79, van den Ouweland AMW80, Peterlongo P81, Putti TC82, Rudolph A29, Sangrajrang S83, Sawyer EJ84, Schmidt MK24, Schmutzler RK85,86,87,88, Shen CY89,90, Hou MF91, Shrubsole MJ1, Southey MC92, Swerdlow A93, Teo SH94,95, Thienpont B63,64, Toland AE96, Tollenaar RAEM97, Tomlinson I98, Truong T46,47, Tseng CC48, Wen W1, Winqvist R99,100, Wu AH48, Yip CH95, Zamora PM101, Zheng Y102, Floris G103, Cheng CY104, Hooning MJ52, Martens JWM52, Seynaeve C52, Kristensen VN76,77,105, Hall P35, Pharoah PDP2,3, Simard J38, Chenevix-Trench G6,106, Dunning AM3, Antoniou AC2, Easton DF2,3, Cai Q1, Long J1.

Author information

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

PMID:
27087578
PMCID:
PMC5110427
DOI:
10.1002/ijc.30150
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center