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PLoS One. 2016 Aug 24;11(8):e0160316. doi: 10.1371/journal.pone.0160316. eCollection 2016.

Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

Horne HN1,2, Chung CC1, Zhang H1, Yu K1, Prokunina-Olsson L1, Michailidou K3, Bolla MK3, Wang Q3, Dennis J3, Hopper JL4, Southey MC5, Schmidt MK6, Broeks A6, Muir K7,8, Lophatananon A7, Fasching PA9,10, Beckmann MW9, Fletcher O11,12, Johnson N11,12, Sawyer EJ13, Tomlinson I14, Burwinkel B15,16, Marme F15,17, Guénel P18,19, Truong T18,19, Bojesen SE20,21,22, Flyger H23, Benitez J24,25, González-Neira A24, Anton-Culver H26, Neuhausen SL27, Brenner H28,29,30, Arndt V28, Meindl A31, Schmutzler RK32,33,34,35, Brauch H30,36,37, Hamann U38, Nevanlinna H39, Khan S39, Matsuo K40, Iwata H41, Dörk T42, Bogdanova NV43, Lindblom A44, Margolin S45, Mannermaa A46,47,48, Kosma VM46,47,48, Chenevix-Trench G49; kConFab/AOCS Investigators, Wu AH50, Ven den Berg D50, Smeets A51, Zhao H52,53, Chang-Claude J54,55, Rudolph A54, Radice P56, Barile M57, Couch FJ58, Vachon C59, Giles GG4,60, Milne RL4,60, Haiman CA50, Marchand LL61, Goldberg MS62,63, Teo SH64,65, Taib NA65, Kristensen V66,67,68, Borresen-Dale AL66,67, Zheng W69, Shrubsole M69, Winqvist R70,71, Jukkola-Vuorinen A72, Andrulis IL73,74, Knight JA75,76, Devilee P77,78, Seynaeve C79, García-Closas M1,80, Czene K81, Darabi H81, Hollestelle A79, Martens JW79, Li J81, Lu W82, Shu XO69, Cox A83, Cross SS84, Blot W69,85, Cai Q69, Shah M86, Luccarini C86, Baynes C86, Harrington P86, Kang D87,88,89, Choi JY88,89, Hartman M90,91, Chia KS90, Kabisch M38, Torres D38,92, Jakubowska A93, Lubinski J93, Sangrajrang S94, Brennan P95, Slager S59, Yannoukakos D96, Shen CY97,98, Hou MF99, Swerdlow A12,80, Orr N11, Simard J100, Hall P81, Pharoah PD3,86, Easton DF3,86, Chanock SJ1, Dunning AM86, Figueroa JD1,101,102.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States of America.
2
Food and Drug Administration, Silver Spring, MD, United States of America.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
4
Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
5
Department of Pathology, The University of Melbourne, Melbourne, Australia.
6
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
7
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
8
Institute of Population Health, University of Manchester, Manchester, UK.
9
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
10
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, United States of America.
11
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
12
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
13
Research Oncology, Guy's Hospital, King's College London, London, UK.
14
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
15
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
16
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
17
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
18
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
19
University Paris-Sud, Villejuif, France.
20
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
21
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
22
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
23
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
24
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
25
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
26
Department of Epidemiology, University of California Irvine, Irvine, CA, United States of America.
27
Beckman Research Institute of City of Hope, Duarte, CA, United States of America.
28
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
29
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
30
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
31
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
32
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
33
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
34
Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
35
Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.
36
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
37
University of Tübingen, Tübingen, Germany.
38
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
39
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
40
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
41
Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan.
42
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
43
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
44
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
45
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
46
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
47
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
48
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
49
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
50
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America.
51
University Hospital Gashuisberg, Leuven, Belgium.
52
Vesalius Research Center, Leuven, Belgium.
53
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
54
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
55
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
56
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
57
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
58
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America.
59
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.
60
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
61
University of Hawaii Cancer Center, Honolulu, HI, United States of America.
62
Department of Medicine, McGill University, Montreal, Canada.
63
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
64
Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia.
65
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, KualaLumpur, Malaysia.
66
Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway.
67
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
68
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
69
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
70
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
71
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
72
Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.
73
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
74
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
75
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
76
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
77
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
78
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
79
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
80
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
81
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
82
Shanghai Center for Disease Control and Prevention, Shanghai, China.
83
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
84
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
85
International Epidemiology Institute, Rockville, MD, United States of America.
86
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
87
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
88
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
89
Cancer Research Institute, Seoul National University, Seoul, Korea.
90
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
91
Department of Surgery, National University Health System, Singapore, Singapore.
92
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
93
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
94
National Cancer Institute, Bangkok, Thailand.
95
International Agency for Research on Cancer, Lyon, France.
96
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
97
School of Public Health, China Medical University, Taichung, Taiwan.
98
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
99
Cancer Center and Department of Surgery, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
100
Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
101
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
102
Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK.

Abstract

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

PMID:
27556229
PMCID:
PMC4996485
DOI:
10.1371/journal.pone.0160316
[Indexed for MEDLINE]
Free PMC Article

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