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Hum Mol Genet. 2014 Nov 15;23(22):6034-46. doi: 10.1093/hmg/ddu300. Epub 2014 Jun 13.

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Purrington KS1, Slettedahl S2, Bolla MK3, Michailidou K3, Czene K4, Nevanlinna H5, Bojesen SE6, Andrulis IL7, Cox A8, Hall P4, Carpenter J9, Yannoukakos D10, Haiman CA11, Fasching PA12, Mannermaa A13, Winqvist R14, Brenner H15, Lindblom A16, Chenevix-Trench G17, Benitez J18, Swerdlow A19, Kristensen V20, Guénel P21, Meindl A22, Darabi H4, Eriksson M4, Fagerholm R23, Aittomäki K24, Blomqvist C25, Nordestgaard BG26, Nielsen SF27, Flyger H28, Wang X29, Olswold C2, Olson JE2, Mulligan AM30, Knight JA31, Tchatchou S32, Reed MW8, Cross SS33, Liu J34, Li J34, Humphreys K4, Clarke C35, Scott R36; ABCTB Investigators, Fostira F10, Fountzilas G37, Konstantopoulou I10, Henderson BE11, Schumacher F11, Le Marchand L38, Ekici AB39, Hartmann A40, Beckmann MW41, Hartikainen JM13, Kosma VM13, Kataja V42, Jukkola-Vuorinen A43, Pylkäs K14, Kauppila S44, Dieffenbach AK15, Stegmaier C45, Arndt V46, Margolin S47; Australian Ovarian Cancer Study Group; kConFab Investigators, Balleine R48, Arias Perez JI49, Pilar Zamora M50, Menéndez P51, Ashworth A52, Jones M53, Orr N52, Arveux P54, Kerbrat P55, Truong T21, Bugert P56, Toland AE57, Ambrosone CB58, Labrèche F59, Goldberg MS60, Dumont M61, Ziogas A62, Lee E11, Dite GS63, Apicella C63, Southey MC64, Long J65, Shrubsole M57, Deming-Halverson S65, Ficarazzi F66, Barile M67, Peterlongo P68, Durda K69, Jaworska-Bieniek K69, Tollenaar RA70, Seynaeve C71; GENICA Network, Brüning T72, Ko YD73, Van Deurzen CH74, Martens JW75, Kriege M75, Figueroa JD76, Chanock SJ76, Lissowska J77, Tomlinson I78, Kerin MJ79, Miller N79, Schneeweiss A80, Tapper WJ81, Gerty SM81, Durcan L81, Mclean C82, Milne RL83, Baglietto L83, dos Santos Silva I84, Fletcher O85, Johnson N85, Van'T Veer LJ86, Cornelissen S86, Försti A87, Torres D88, Rüdiger T89, Rudolph A90, Flesch-Janys D91, Nickels S90, Weltens C92, Floris G92, Moisse M93, Dennis J3, Wang Q3, Dunning AM94, Shah M94, Brown J3, Simard J61, Anton-Culver H62, Neuhausen SL95, Hopper JL63, Bogdanova N96, Dörk T97, Zheng W65, Radice P98, Jakubowska A69, Lubinski J69, Devillee P99, Brauch H100, Hooning M75, García-Closas M52, Sawyer E101, Burwinkel B102, Marmee F80, Eccles DM81, Giles GG83, Peto J84, Schmidt M86, Broeks A86, Hamann U103, Chang-Claude J90, Lambrechts D93, Pharoah PD104, Easton D104, Pankratz VS2, Slager S2, Vachon CM2, Couch FJ105.

Author information

1
Department of Health Sciences Research, Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, USA.
2
Department of Health Sciences Research.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care.
4
Department of Medical Epidemiology and Biostatistics.
5
Department of Obstetrics and Gynecology.
6
Copenhagen General Population Study, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
7
Ontario Cancer Genetics Network, Department of Molecular Genetics.
8
CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology.
9
Australian Breast Cancer Tissue Bank.
10
Molecular Diagnostics Laboratory INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
11
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
12
University Breast Center Franconia, Department of Gynecology and Obstetrics, David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, USA.
13
School of Medicine, Institute of Clinical Medicine, Oncology, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland, Imaging Center, Department of Clinical Pathology.
14
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu University Hospital/NordLab Oulu, Oulu, Finland.
15
Division of Clinical Epidemiology and Aging Research, German Cancer Consortium (DKTK), Heidelberg, Germany.
16
Department of Molecular Medicine and Surgery.
17
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
18
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
19
Division of Genetics and Epidemiology, Division of Breast Cancer Research, Institute of Cancer Research, Sutton, UK.
20
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway, Faculty of Medicine (Faculty Division Ahus), University of Oslo (UiO), Oslo, Norway.
21
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.
22
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
23
Department of Obstetrics and Gynecology, Oncology and Clinical Genetics.
24
Department of Clinical Genetics.
25
Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
26
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
27
Copenhagen General Population Study.
28
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
29
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
30
Department of Laboratory Medicine and Pathobiology, Laboratory Medicine Program, University Health Network, Toronto, Canada.
31
Prosserman Centre for Health Research, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
32
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
33
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
34
Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore.
35
Westmead Institute for Cancer Research, Sydney Medical School Westmead, University of Sydney at the Westmead Millennium Institute, Westmead, Australia.
36
Division of Genetics, Hunter Area Pathology Service and University of Newcastle, Newcastle, Australia.
37
Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
38
Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, USA.
39
Institute of Human Genetics.
40
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
41
University Breast Center Franconia, Department of Gynecology and Obstetrics.
42
School of Medicine, Institute of Clinical Medicine, Oncology, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland, Cancer Center, Kuopio University Hospital, Kuopio, Finland.
43
Department of Oncology.
44
Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.
45
Saarland Cancer Registry, Saarbrücken, Germany.
46
Division of Clinical Epidemiology and Aging Research.
47
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
48
Westmead Millenium Institute for Medical Research, Sydney, Australia.
49
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
50
Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
51
Servicio de Anatomía Patológica.
52
Breakthrough Breast Cancer Research Centre and Division of Breast Cancer Research.
53
Division of Genetics and Epidemiology.
54
Center Georges-Francois Leclerc, Registry of Gynecologic Tumors, Dijon, France.
55
Centre Eugène Marquis, Department of Medical Oncology, Rennes, France.
56
German Red Cross Blood Service of Baden-Württemberg-Hessen, Mannheim, Germany, Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, Heidelberg University, Heidelberg, Germany.
57
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
58
Roswell Park Cancer Institute, Buffalo, USA.
59
Department of Environmental & Occupational Health and of Social & Preventive Medicine, School of Public Health, Université de Montréal, Montreal, Canada.
60
Department of Medicine, McGill University, Montreal, Canada, Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Canada.
61
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Canada.
62
Department of Epidemiology, University of California Irvine, Irvine, USA.
63
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health.
64
Department of Pathology.
65
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, USA.
66
Cogentech Cancer Genetic Test Laboratory, Milan, Italy, IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
67
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy.
68
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
69
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
70
Department of Surgical Oncology.
71
Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Centrer, Rotterdam, The Netherlands.
72
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany.
73
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.
74
Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
75
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
76
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, USA.
77
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland.
78
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
79
Clinical Science Institute, University Hospital Galway, Galway, Ireland.
80
Department of Obstetrics and Gynecology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
81
Faculty of Medicine, University of Southampton, Southampton, UK.
82
Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
83
Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia, Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia.
84
Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
85
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
86
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
87
Division of Molecular Genetic Epidemiology, Center for Primary Health Care Research, University of Lund, Malmö, Sweden.
88
Molecular Genetics of Breast Cancer, Institute of Human Genetics, Pontificia University Javeriana, Bogota, Colombia.
89
Institute of Pathology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
90
Division of Cancer Epidemiology.
91
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
92
Universital Hospital Gasthuisberg, Leuven, Belgium.
93
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium, Vesalius Research Center (VRC), VIB, Leuven, Belgium.
94
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
95
Beckman Research Institute of City of Hope, Duarte, USA.
96
Department of Radiation Oncology.
97
Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
98
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy and.
99
Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
100
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany.
101
Division of Cancer Studies, Kings College London, Guy's Hospital, London, UK.
102
Department of Obstetrics and Gynecology, Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
103
Molecular Genetics of Breast Cancer.
104
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
105
Department of Health Sciences Research, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA, couch.fergus@mayo.edu.

Abstract

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

PMID:
24927736
PMCID:
PMC4204763
DOI:
10.1093/hmg/ddu300
[Indexed for MEDLINE]
Free PMC Article

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