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Hum Mol Genet. 2015 May 15;24(10):2966-84. doi: 10.1093/hmg/ddv035. Epub 2015 Feb 4.

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

Orr N1, Dudbridge F2, Dryden N3, Maguire S3, Novo D3, Perrakis E3, Johnson N3, Ghoussaini M4, Hopper JL5, Southey MC6, Apicella C5, Stone J7, Schmidt MK8, Broeks A8, Van't Veer LJ8, Hogervorst FB8, Fasching PA9, Haeberle L10, Ekici AB11, Beckmann MW10, Gibson L2, Aitken Z2, Warren H12, Sawyer E13, Tomlinson I14, Kerin MJ15, Miller N15, Burwinkel B16, Marme F17, Schneeweiss A17, Sohn C18, Guénel P19, Truong T19, Cordina-Duverger E19, Sanchez M19, Bojesen SE20, Nordestgaard BG20, Nielsen SF20, Flyger H21, Benitez J22, Zamora MP23, Arias Perez JI24, Menéndez P25, Anton-Culver H26, Neuhausen SL27, Brenner H28, Dieffenbach AK28, Arndt V29, Stegmaier C30, Hamann U31, Brauch H32, Justenhoven C33, Brüning T34, Ko YD, Nevanlinna H35, Aittomäki K36, Blomqvist C37, Khan S35, Bogdanova N38, Dörk T39, Lindblom A40, Margolin S41, Mannermaa A42, Kataja V43, Kosma VM42, Hartikainen JM42, Chenevix-Trench G44, Beesley J, Lambrechts D45, Moisse M45, Floris G46, Beuselinck B46, Chang-Claude J47, Rudolph A47, Seibold P47, Flesch-Janys D48, Radice P49, Peterlongo P50, Peissel B51, Pensotti V52, Couch FJ53, Olson JE54, Slettedahl S54, Vachon C54, Giles GG55, Milne RL55, McLean C56, Haiman CA57, Henderson BE57, Schumacher F57, Le Marchand L58, Simard J59, Goldberg MS60, Labrèche F61, Dumont M59, Kristensen V62, Alnæs GG63, Nord S63, Borresen-Dale AL62, Zheng W64, Deming-Halverson S64, Shrubsole M64, Long J64, Winqvist R65, Pylkäs K65, Jukkola-Vuorinen A66, Grip M67, Andrulis IL68, Knight JA69, Glendon G70, Tchatchou S71, Devilee P72, Tollenaar RA73, Seynaeve CM74, Van Asperen CJ75, Garcia-Closas M76, Figueroa J77, Chanock SJ77, Lissowska J78, Czene K79, Darabi H79, Eriksson M79, Klevebring D78, Hooning MJ74, Hollestelle A74, van Deurzen CH80, Kriege M74, Hall P79, Li J81, Liu J81, Humphreys K79, Cox A82, Cross SS83, Reed MW84, Pharoah PD4, Dunning AM4, Shah M4, Perkins BJ4, Jakubowska A85, Lubinski J85, Jaworska-Bieniek K85, Durda K85, Ashworth A3, Swerdlow A86, Jones M87, Schoemaker MJ86, Meindl A88, Schmutzler RK89, Olswold C53, Slager S53, Toland AE90, Yannoukakos D91, Muir K92, Lophatananon A93, Stewart-Brown S93, Siriwanarangsan P94, Matsuo K95, Ito H96, Iwata H97, Ishiguro J97, Wu AH57, Tseng CC57, Van Den Berg D57, Stram DO57, Teo SH98, Yip CH99, Kang P100, Ikram MK101, Shu XO64, Lu W102, Gao YT103, Cai H64, Kang D104, Choi JY105, Park SK104, Noh DY106, Hartman M107, Miao H108, Lim WY108, Lee SC109, Sangrajrang S110, Gaborieau V111, Brennan P111, Mckay J111, Wu PE112, Hou MF113, Yu JC114, Shen CY115, Blot W116, Cai Q64, Signorello LB117, Luccarini C4, Bayes C4, Ahmed S4, Maranian M4, Healey CS4, González-Neira A118, Pita G118, Alonso MR118, Álvarez N118, Herrero D118, Tessier DC119, Vincent D119, Bacot F119, Hunter DJ120, Lindstrom S120, Dennis J121, Michailidou K121, Bolla MK121, Easton DF122, dos Santos Silva I2, Fletcher O3, Peto J2; GENICA Network; kConFab Investigators; Australian Ovarian Cancer Study Group.

Author information

1
The Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research and nicholas.orr@icr.ac.uk.
2
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
3
The Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research and.
4
Centre for Cancer Genetic Epidemiology, Department of Oncology and.
5
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and.
6
Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.
7
Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, WA, Australia.
8
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
9
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen and David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
10
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen and.
11
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
12
Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
13
Division of Cancer Studies, Kings College London, Guy's Hospital, London, UK.
14
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, UK.
15
Clinical Science Institute, University Hospital Galway, Galway, Ireland.
16
Department of Obstetrics and Gynecology and Molecular Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
17
Department of Obstetrics and Gynecology and National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany.
18
Department of Obstetrics and Gynecology and.
19
Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France, University Paris-Sud, UMRS 1018, Villejuif, France.
20
Copenhagen General Population Study and Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
21
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
22
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain, Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain.
23
Servicio de Oncología Médica, Hospital Universitario La Paz, 28046 Madrid, Spain.
24
Servicio de Cirugía General y Especialidades and.
25
Servicio de Anatomía Patológica, Hospital Monte Naranco, 33012 Oviedo, Spain.
26
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
27
Beckman Research Institute of City of Hope, Duarte, CA, USA.
28
Division of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK).
29
Division of Clinical Epidemiology and Aging Research.
30
Saarland Cancer Registry, Saarbrücken, Germany.
31
Molecular Genetics of Breast Cancer and.
32
German Cancer Consortium (DKTK), Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany.
33
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany.
34
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany.
35
Department of Obstetrics and Gynecology.
36
Department of Clinical Genetics and.
37
Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
38
Department of Radiation Oncology and Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
39
Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
40
Department of Molecular Medicine and Surgery and.
41
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
42
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Imaging Center, Department of Clinical Pathology and.
43
School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland, Biocenter Kuopio, Cancer Center of Eastern Finland, Kuopio University Hospital, Kuopio, Finland, Central Finland Health Care District, Jyväskylä Central Hospital, Jyväskylä, Finland.
44
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
45
Vesalius Research Center (VRC), VIB, Leuven, Belgium, Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
46
University Hospital Gasthuisberg, Leuven, Belgium.
47
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
48
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
49
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine and.
50
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
51
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
52
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy, Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
53
Department of Laboratory Medicine and Pathology and.
54
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
55
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia.
56
Anatomical Pathology, The Alfred Hospital, Melbourne, VIC, Australia.
57
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
58
Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, USA.
59
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC, Canada.
60
Department of Medicine, McGill University, Montreal, QC, Canada, Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada.
61
Département de Médecine Sociale et Préventive, Département de Santé Environnementale et Santé au travail, Université de Montréal, Montreal, QC, Canada.
62
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, N-0310 Oslo, Norway, Institute of Clinical Medicine, University of Oslo (UiO), 0450 Oslo, Norway.
63
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, N-0310 Oslo, Norway.
64
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
65
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Genetics and Biocenter Oulu.
66
Department of Oncology and.
67
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
68
Ontario Cancer Genetics Network and Department of Molecular Genetics and.
69
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
70
Ontario Cancer Genetics Network and.
71
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
72
Department of Human Genetics and Department of Pathology and.
73
Department of Surgical Oncology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
74
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
75
Department of Clinical Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
76
The Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research and Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
77
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
78
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland.
79
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
80
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
81
Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore.
82
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
83
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
84
Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, UK.
85
Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland.
86
Division of Breast Cancer Research and Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
87
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
88
Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany.
89
Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany.
90
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
91
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens, Greece.
92
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK, Institute of Population Health, University of Manchester, Manchester, UK.
93
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
94
Ministry of Public Health, Nonthaburi, Thailand.
95
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
96
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
97
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
98
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia, Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
99
Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
100
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia.
101
Singapore Eye Research Institute, National University of Singapore, 168751 Singapore, Singapore.
102
Shanghai Center for Disease Control and Prevention, Shanghai, China.
103
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
104
Department of Preventive Medicine and Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea, Cancer Research Institute, Seoul National University, Seoul, Korea.
105
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea, Cancer Research Institute, Seoul National University, Seoul, Korea.
106
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
107
Saw Swee Hock School of Public Health and Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, National University Health System, Singapore, Singapore.
108
Saw Swee Hock School of Public Health and National University Health System, Singapore, Singapore.
109
Department of Haematology-Oncology, National University Health System, Singapore, Singapore, Cancer Science Institute of Singapore, National University Singapore, Singapore, Singapore.
110
National Cancer Institute, Bangkok, Thailand.
111
International Agency for Research on Cancer, Lyon, France.
112
Taiwan Biobank and Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
113
Cancer Center and Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung 804, Taiwan.
114
Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan.
115
Cancer Center and Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung 804, Taiwan, School of Public Health, China Medical University, Taichung 404, Taiwan.
116
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA, International Epidemiology Institute, Rockville, MD, USA.
117
Dana-Farber/Harvard Cancer Center, Boston, MA, USA, Department of Epidemiology and.
118
Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain and.
119
Centre d'innovation Génome Québec et Université McGill, Montréal, QC, Canada.
120
Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA.
121
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
122
Centre for Cancer Genetic Epidemiology, Department of Oncology and Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

PMID:
25652398
PMCID:
PMC4406292
DOI:
10.1093/hmg/ddv035
[Indexed for MEDLINE]
Free PMC Article

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