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Carcinogenesis. 2015 Feb;36(2):256-71. doi: 10.1093/carcin/bgu326. Epub 2015 Jan 13.

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

Kabisch M1, Lorenzo Bermejo J2, Dünnebier T1, Ying S1, Michailidou K3, Bolla MK3, Wang Q3, Dennis J3, Shah M4, Perkins BJ4, Czene K5, Darabi H5, Eriksson M5, Bojesen SE6, Nordestgaard BG6, Nielsen SF6, Flyger H7, Lambrechts D8, Neven P9, Peeters S9, Weltens C9, Couch FJ10, Olson JE11, Wang X10, Purrington K12, Chang-Claude J13, Rudolph A13, Seibold P13, Flesch-Janys D14, Peto J15, dos-Santos-Silva I15, Johnson N16, Fletcher O16, Nevanlinna H17, Muranen TA17, Aittomäki K18, Blomqvist C19, Schmidt MK20, Broeks A20, Cornelissen S20, Hogervorst FB20, Li J21, Brand JS5, Humphreys K5, Guénel P22, Truong T22, Menegaux F22, Sanchez M22, Burwinkel B23, Marmé F24, Yang R23, Bugert P25, González-Neira A26, Benitez J, Pilar Zamora M27, Arias Perez JI28, Cox A29, Cross SS30, Reed MW29, Andrulis IL31, Knight JA32, Glendon G33, Tchatchou S34, Sawyer EJ35, Tomlinson I36, Kerin MJ37, Miller N37; kConFab Investigators; Australian Ovarian Cancer Study Group, Haiman CA38, Schumacher F38, Henderson BE38, Le Marchand L39, Lindblom A40, Margolin S41, Hooning MJ42, Hollestelle A42, Kriege M42, Koppert LB43, Hopper JL44, Southey MC45, Tsimiklis H45, Apicella C44, Slettedahl S11, Toland AE46, Vachon C11, Yannoukakos D47, Giles GG48, Milne RL48, McLean C49, Fasching PA, Ruebner M50, Ekici AB51, Beckmann MW50, Brenner H52, Dieffenbach AK52, Arndt V53, Stegmaier C54, Ashworth A16, Orr N16, Schoemaker MJ55, Swerdlow A56, García-Closas M57, Figueroa J58, Chanock SJ58, Lissowska J59, Goldberg MS60, Labrèche F61, Dumont M62, Winqvist R63, Pylkäs K63, Jukkola-Vuorinen A64, Grip M65, Brauch H, Brüning T66, Ko YD67; GENICA Network, Radice P68, Peterlongo P69, Scuvera G70, Fortuzzi S71, Bogdanova N72, Dörk T73, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Devilee P74, Tollenaar RA75, Seynaeve C42, Van Asperen CJ76, Jakubowska A77, Lubinski J77, Jaworska-Bieniek K77, Durda K77, Zheng W78, Shrubsole MJ78, Cai Q78, Torres D79, Anton-Culver H80, Kristensen V, Bacot F81, Tessier DC81, Vincent D81, Luccarini C4, Baynes C4, Ahmed S4, Maranian M4, Simard J62, Chenevix-Trench G82, Hall P5, Pharoah PD28, Dunning AM4, Easton DF28, Hamann U83.

Author information

1
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
Institute of Medical Biometry and Informatics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
3
Department of Public Health and Primary Care and.
4
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, CB1 8RN, UK.
5
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE-17177, Sweden.
6
Copenhagen General Population Study, Department of Clinical Biochemistry, and.
7
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
8
Vesalius Research Center, VIB, 3000 Leuven, Belgium, Department of Oncology, Laboratory for Translational Genetics, University of Leuven, 3000 Leuven, Belgium.
9
Department of Oncology, KU Leuven (University of Leuven), Multidisciplinary Breast Center, University Hospitals Leuven, 3000 Leuven, Belgium.
10
Department of Laboratory Medicine and Pathology and.
11
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
12
Karmanos Cancer Institute, Detroit, MI 48201, USA.
13
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
14
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, 20246 Hamburg, Germany.
15
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
16
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
17
Department of Obstetrics and Gynecology.
18
Department of Clinical Genetics and.
19
Department of Oncology, University of Helsinki and Helsinki University Central Hospital, FI-00029 Helsinki, Finland.
20
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
21
Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore.
22
National Institute of Health and Medical Research, Center for Research in Epidemiology and Population Health, Environmental Epidemiology of Cancer, 94807 Villejuif, France, University Paris-Sud, 94807 Villejuif, France.
23
Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany, Molecular Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
24
Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany, National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany.
25
Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
26
Human Genotyping-CEGEN Unit and.
27
Servicio de Oncología Médica, Hospital Universitario La Paz, 28046 Madrid, Spain.
28
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, 33012 Oviedo, Spain.
29
Department of Oncology, University of Sheffield, Sheffield, S10 2RX, UK.
30
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
31
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada, Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
32
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
33
ON Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
34
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
35
Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London SE1 9RT, UK.
36
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
37
Clinical Science Institute, University Hospital Galway, Galway, Ireland.
38
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
39
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
40
Department of Molecular Medicine and Surgery and.
41
Department of Oncology - Pathology, Karolinska Institutet, Stockholm SE-17177, Sweden.
42
Department of Medical Oncology and.
43
Department of Surgical Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands.
44
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and.
45
Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
46
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
47
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, 153 10 Athens, Greece.
48
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3053, Australia.
49
Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia.
50
Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
51
Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany, Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
52
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
53
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
54
Saarland Cancer Registry, 66119 Saarbrücken, Germany.
55
Division of Genetics and Epidemiology and.
56
Division of Genetics and Epidemiology and Division of Breast Cancer Research, Institute of Cancer Research, London, SM2 5NG, UK.
57
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK, Division of Genetics and Epidemiology and.
58
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.
59
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland.
60
Department of Medicine, McGill University, Montreal, QC, H3G 2M1, Canada, Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC H3G 2M1, Canada.
61
Département de santé environnementale et santé au travail, Département de médecine sociale et preventive, École de santé publique, Université de Montréal, Montreal, QC, H3T 1A8, Canada.
62
Centre Hospitalier Universitaire de Québec Research Center and Laval University, QC, G1V 4G2, Canada.
63
Department of Clinical Chemistry and Biocenter Oulu, Laboratory of Cancer Genetics and Tumor Biology, University of Oulu, NordLab Oulu/Oulu University Hospital, FI-90220 Oulu, Finland.
64
Department of Oncology and.
65
Department of Surgery, Oulu University Hospital, University of Oulu, FI-90220 Oulu, Finland.
66
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789 Bochum, Germany.
67
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53113 Bonn, Germany.
68
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy.
69
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy.
70
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy.
71
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy, Cogentech Cancer Genetic Test Laboratory, 20139 Milan, Italy.
72
Department of Radiation Oncology and.
73
Department of Obstetrics and Gynaecology, Hannover Medical School, 30625 Hannover, Germany.
74
Department of Human Genetics and Department of Pathology.
75
Department of Surgical Oncology and.
76
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.
77
Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland.
78
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
79
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, Institute of Human Genetics, Pontificia Universidad Javeriana, 11001000 Bogotá, Colombia.
80
Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA.
81
McGill University and Génome Québec Innovation Centre, Montréal, QC H3A 0G1, Canada and.
82
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
83
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, u.hamann@dkfz-heidelberg.de.

Abstract

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.

PMID:
25586992
PMCID:
PMC4335262
DOI:
10.1093/carcin/bgu326
[Indexed for MEDLINE]
Free PMC Article

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