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Hum Mol Genet. 2015 Jan 1;24(1):285-98. doi: 10.1093/hmg/ddu431. Epub 2014 Aug 28.

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Lin WY1, Camp NJ2, Ghoussaini M3, Beesley J4, Michailidou K3, Hopper JL5, Apicella C5, Southey MC6, Stone J7, Schmidt MK8, Broeks A8, Van't Veer LJ8, Th Rutgers EJ8, Muir K9, Lophatananon A10, Stewart-Brown S10, Siriwanarangsan P11, Fasching PA12, Haeberle L13, Ekici AB14, Beckmann MW13, Peto J15, Dos-Santos-Silva I15, Fletcher O16, Johnson N16, Bolla MK3, Wang Q3, Dennis J3, Sawyer EJ17, Cheng T18, Tomlinson I18, Kerin MJ19, Miller N19, Marmé F20, Surowy HM21, Burwinkel B21, Guénel P22, Truong T22, Menegaux F22, Mulot C23, Bojesen SE24, Nordestgaard BG24, Nielsen SF25, Flyger H26, Benitez J27, Zamora MP28, Arias Perez JI29, Menéndez P30, González-Neira A31, Pita G31, Alonso MR31, Alvarez N31, Herrero D31, Anton-Culver H32, Brenner H33, Dieffenbach AK33, Arndt V34, Stegmaier C35, Meindl A36, Lichtner P37, Schmutzler RK38, Müller-Myhsok B39, Brauch H40, Brüning T41, Ko YD42; GENICA Network, Tessier DC43, Vincent D43, Bacot F43, Nevanlinna H44, Aittomäki K45, Blomqvist C46, Khan S44, Matsuo K47, Ito H48, Iwata H49, Horio A49, Bogdanova NV50, Antonenkova NN51, Dörk T52, Lindblom A53, Margolin S54, Mannermaa A55, Kataja V56, Kosma VM55, Hartikainen JM55; kConFab Investigators; Australian Ovarian Cancer Study Group, Wu AH57, Tseng CC57, Van Den Berg D57, Stram DO57, Neven P58, Wauters E59, Wildiers H60, Lambrechts D61, Chang-Claude J62, Rudolph A62, Seibold P62, Flesch-Janys D63, Radice P64, Peterlongo P65, Manoukian S66, Bonanni B67, Couch FJ68, Wang X68, Vachon C69, Purrington K70, Giles GG71, Milne RL71, Mclean C72, Haiman CA57, Henderson BE57, Schumacher F57, Le Marchand L73, Simard J74, Goldberg MS75, Labrèche F76, Dumont M74, Teo SH77, Yip CH78, Hassan N77, Vithana EN79, Kristensen V80, Zheng W81, Deming-Halverson S81, Shrubsole MJ81, Long J81, Winqvist R82, Pylkäs K82, Jukkola-Vuorinen A83, Kauppila S84, Andrulis IL85, Knight JA86, Glendon G87, Tchatchou S88, Devilee P89, Tollenaar RA90, Seynaeve C91, Van Asperen CJ92, García-Closas M93, Figueroa J94, Lissowska J95, Brinton L94, Czene K96, Darabi H96, Eriksson M96, Brand JS96, Hooning MJ91, Hollestelle A91, Van Den Ouweland AM97, Jager A91, Li J98, Liu J99, Humphreys K96, Shu XO81, Lu W98, Gao YT100, Cai H81, Cross SS101, Reed MW102, Blot W103, Signorello LB103, Cai Q81, Pharoah PD104, Perkins B105, Shah M105, Blows FM105, Kang D106, Yoo KY107, Noh DY108, Hartman M109, Miao H110, Chia KS110, Putti TC111, Hamann U112, Luccarini C105, Baynes C105, Ahmed S105, Maranian M105, Healey CS105, Jakubowska A113, Lubinski J113, Jaworska-Bieniek K113, Durda K113, Sangrajrang S114, Gaborieau V115, Brennan P115, Mckay J115, Slager S69, Toland AE116, Yannoukakos D117, Shen CY118, Hsiung CN119, Wu PE120, Ding SL121, Ashworth A122, Jones M123, Orr N124, Swerdlow AJ125, Tsimiklis H126, Makalic E127, Schmidt DF127, Bui QM127, Chanock SJ94, Hunter DJ128, Hein R129, Dahmen N130, Beckmann L131, Aaltonen K44, Muranen TA44, Heikkinen T44, Irwanto A99, Rahman N123, Turnbull CA123; Breast and Ovarian Cancer Susceptibility (BOCS) Study, Waisfisz Q132, Meijers-Heijboer HE132, Adank MA132, Van Der Luijt RB133, Hall P96, Chenevix-Trench G4, Dunning A105, Easton DF104, Cox A134.

Author information

1
Department of Oncology, University of Sheffield Medical School, Sheffield S10 2RX, UK Department of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan County 333, Taiwan.
2
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108-1266, USA.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care.
4
Department of Genetics.
5
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health.
6
Department of Pathology.
7
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health.
8
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, the Netherlands.
9
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK Institute of Population Health, University of Manchester, Manchester M13 9QQ, UK.
10
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
11
Ministry of Public Health, Nonthaburi 11000, Thailand.
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, Los Angeles, CA 90095, USA.
13
University Breast Center Franconia, Department of Gynecology and Obstetrics.
14
Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen D-91054, Germany.
15
Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
16
Breakthrough Breast Cancer Research Centre.
17
Division of Cancer Studies, Kings College London, Guy's Hospital, London SE1 9RT, UK.
18
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
19
School of Medicine, National University of Ireland, Galway, Ireland.
20
Department of Obstetrics and Gynecology National Center for Tumor Diseases, University of Heidelberg, Heidelberg 69117, Germany.
21
Department of Obstetrics and Gynecology Molecular Epidemiology Group.
22
Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif 94807, France University Paris-Sud, UMRS 1018, Villejuif 94807, France.
23
Université Paris Sorbonne Cité, UMR-S775 Inserm, Paris 75015, France.
24
Copenhagen General Population Study, Herlev Hospital, 2730 Herlev, Copenhagen, Denmark Department of Clinical Biochemistry Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
25
Copenhagen General Population Study, Herlev Hospital, 2730 Herlev, Copenhagen, Denmark Department of Clinical Biochemistry.
26
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen 2100, Denmark.
27
Human Genetics Group, Human Cancer Genetics Program Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia 28029, Spain.
28
Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid 28046, Spain.
29
Servicio de Cirugía General y Especialidades.
30
Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo 33012, Spain.
31
Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain.
32
Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA.
33
Division of Clinical Epidemiology and Aging Research German Cancer Consortium (DKTK), Heidelberg, Germany.
34
Division of Clinical Epidemiology and Aging Research.
35
Saarland Cancer Registry, Saarbrücken 66024, Germany.
36
Division of Gynaecology and Obstetrics.
37
Insitute of Human Genetics, Technische Universität München, Munich D-80333, Germany.
38
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, 50932 Cologne, Germany.
39
Max Planck Institute of Psychiatry, Munich 80804, Germany.
40
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart 70376, Germany University of Tübingen, Tübingen 72074, Germany German Cancer Consortium (DKTK).
41
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum D-44789, Germany.
42
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn 53113, Germany.
43
Centre D'innovation Génome Québec et Université McGill, Montréal, QC, Canada H3A 0G1.
44
Department of Obstetrics and Gynecology Helsinki University Central Hospital, Helsinki 00029, Finland.
45
Department of Clinical Genetics Helsinki University Central Hospital, Helsinki 00029, Finland.
46
Department of Oncology, University of Helsinki Helsinki University Central Hospital, Helsinki 00029, Finland.
47
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan.
48
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
49
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
50
Department of Obstetrics and Gynaecology Department of Radiation Oncology, Hannover Medical School, Hannover 30625, Germany.
51
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus.
52
Department of Obstetrics and Gynaecology.
53
Department of Molecular Medicine and Surgery.
54
Department of Oncology-Pathology.
55
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Cancer Center of Eastern Finland Imaging Center, Department of Clinical Pathology.
56
School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio 70210, Finland Cancer Center, Kuopio University Hospital, Kuopio 70029, Finland.
57
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
58
University Hospital Gashuisberg, Leuven 3000, Belgium.
59
Vesalius Research Center (VRC), VIB, Leuven 3000, Belgium Department of Oncology.
60
Department of General Medical Oncology, University Hospitals Leuven, Leuven 3000, Belgium.
61
Vesalius Research Center (VRC), VIB, Leuven 3000, Belgium Laboratory for Translational Genetics, Department of Oncology.
62
Division of Cancer Epidemiology.
63
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg D-20246, Germany.
64
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine.
65
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan 20139, Italy.
66
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan 20133, Italy.
67
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan 20141, Italy.
68
Department of Laboratory Medicine and Pathology.
69
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
70
Karmanos Cancer Center, Detroit, MI 48201, USA.
71
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3004, Australia.
72
Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
73
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
74
Centre Hospitalier Universitaire de Québec Research Centre and Laval University, Quebec City, QC, Canada G1V 4G2.
75
Department of Medicine, McGill University, Montreal, QC, Canada H3A 0G4 Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC, Canada H3A 1A1.
76
Départements de Santé Environnementale et Santé au Travail et de Médecine Sociale et Préventive, École de Santé Publique, Université de Montréal, Montreal, QC, Canada H3T 1J4.
77
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 50603, Malaysia.
78
Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur 50603, Malaysia.
79
Singapore Eye Research Institute, National University of Singapore, Singapore 119077, Singapore.
80
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo 0372, Norway Faculty of Medicine (Faculty Division Ahus), University of Oslo (UiO), Oslo 0316, Norway.
81
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
82
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, Northern Finland Laboratory Centre NordLab.
83
Department of Oncology.
84
Department of Pathology, Oulu University Hospital, University of Oulu, Oulu 90570, Finland.
85
Ontario Cancer Genetics Network Department of Molecular Genetics.
86
Prosserman Centre for Health Research Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada M5S 2J7.
87
Ontario Cancer Genetics Network.
88
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
89
Department of Human Genetics & Department of Pathology.
90
Department of Surgical Oncology.
91
Family Cancer Clinic, Department of Medical Oncology, Erasmus MC Cancer Institute Rotterdam 3075 EA, The Netherlands.
92
Department of Clinical Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
93
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research Division of Genetics and Epidemiology.
94
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.
95
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw 02-781, Poland.
96
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
97
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam 3075 EA, The Netherlands.
98
Shanghai Center for Disease Control and Prevention, Shanghai 200336, China.
99
Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore.
100
Department of Epidemiology, Shanghai Cancer Institute, Shanghai 220025, China.
101
Department of Neuroscience, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
102
Department of Oncology, University of Sheffield Medical School, Sheffield S10 2RX, UK.
103
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA International Epidemiology Institute, Rockville, MD 20850, USA.
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 CB1 8RN, UK.
105
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
106
Department of Preventive Medicine Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea.
107
Seoul National University College of Medicine, Seoul 110-799, Korea.
108
Department of Surgery.
109
Saw Swee Hock School of Public Health Department of Surgery, Yong Loo Lin School of Medicine National University Health System, Singapore 119228, Singapore.
110
Saw Swee Hock School of Public Health National University Health System, Singapore 119228, Singapore.
111
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
112
Molecular Genetics of Breast Cancer.
113
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-204, Poland.
114
National Cancer Institute, Bangkok 10400, Thailand.
115
International Agency for Research on Cancer, Lyon 69372, France.
116
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
117
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens 153 10, Greece.
118
Institute of Biomedical Sciences College of Public Health, China Medical University, Taichung 40402, Taiwan.
119
Institute of Biomedical Sciences.
120
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
121
Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei 11529, Taiwan.
122
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research.
123
Division of Genetics and Epidemiology.
124
Breakthrough Breast Cancer Research Centre and Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK.
125
Division of Genetics and Epidemiology Division of Breast Cancer Research.
126
Genetic Epidemiology Laboratory, Department of Pathology.
127
Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, Melbourne School of Population Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
128
Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
129
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne 50923, Germany.
130
Department of Psychiatry, University of Mainz, Mainz 55122, Germany.
131
Institute for Quality and Efficiency in Health Care (IQWiG), Cologne 50670, Germany.
132
Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Amsterdam 1081 HZ, The Netherlands and.
133
Department of Medical Genetics, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
134
Department of Oncology, University of Sheffield Medical School, Sheffield S10 2RX, UK a.cox@sheffield.ac.uk.

Abstract

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

PMID:
25168388
PMCID:
PMC4334820
DOI:
10.1093/hmg/ddu431
[Indexed for MEDLINE]
Free PMC Article

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