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

Lin WY 1 , Camp NJ 2 , Ghoussaini M 3 , Beesley J 4 , Michailidou K 3 , Hopper JL 5 Show all authors , Apicella C 5 , Southey MC 6 , Stone J 7 , Schmidt MK 8 , Broeks A 8 , Van't Veer LJ 8 , Th Rutgers EJ 8 , Muir K 9 , Lophatananon A 10 , Stewart-Brown S 10 , Siriwanarangsan P 11 , Fasching PA 12 , Haeberle L 13 , Ekici AB 14 , Beckmann MW 13 , Peto J 15 , Dos-Santos-Silva I 15 , Fletcher O 16 , Johnson N 16 , Bolla MK 3 , Wang Q 3 , Dennis J 3 , Sawyer EJ 17 , Cheng T 18 , Tomlinson I 18 , Kerin MJ 19 , Miller N 19 , Marmé F 20 , Surowy HM 21 , Burwinkel B 21 , Guénel P 22 , Truong T 22 , Menegaux F 22 , Mulot C 23 , Bojesen SE 24 , Nordestgaard BG 24 , Nielsen SF 25 , Flyger H 26 , Benitez J 27 , Zamora MP 28 , Arias Perez JI 29 , Menéndez P 30 , González-Neira A 31 , Pita G 31 , Alonso MR 31 , Alvarez N 31 , Herrero D 31 , Anton-Culver H 32 , Brenner H 33 , Dieffenbach AK 33 , Arndt V 34 , Stegmaier C 35 , Meindl A 36 , Lichtner P 37 , Schmutzler RK 38 , Müller-Myhsok B 39 , Brauch H 40 , Brüning T 41 , Ko YD 42 , GENICA Network , Tessier DC 43 , Vincent D 43 , Bacot F 43 , Nevanlinna H 44 , Aittomäki K 45 , Blomqvist C 46 , Khan S 44 , Matsuo K 47 , Ito H 48 , Iwata H 49 , Horio A 49 , Bogdanova NV 50 , Antonenkova NN 51 , Dörk T 52 , Lindblom A 53 , Margolin S 54 , Mannermaa A 55 , Kataja V 56 , Kosma VM 55 , Hartikainen JM 55 , kConFab Investigators , Australian Ovarian Cancer Study Group , Wu AH 57 , Tseng CC 57 , Van Den Berg D 57 , Stram DO 57 , Neven P 58 , Wauters E 59 , Wildiers H 60 , Lambrechts D 61 , Chang-Claude J 62 , Rudolph A 62 , Seibold P 62 , Flesch-Janys D 63 , Radice P 64 , Peterlongo P 65 , Manoukian S 66 , Bonanni B 67 , Couch FJ 68 , Wang X 68 , Vachon C 69 , Purrington K 70 , Giles GG 71 , Milne RL 71 , Mclean C 72 , Haiman CA 57 , Henderson BE 57 , Schumacher F 57 , Le Marchand L 73 , Simard J 74 , Goldberg MS 75 , Labrèche F 76 , Dumont M 74 , Teo SH 77 , Yip CH 78 , Hassan N 77 , Vithana EN 79 , Kristensen V 80 , Zheng W 81 , Deming-Halverson S 81 , Shrubsole MJ 81 , Long J 81 , Winqvist R 82 , Pylkäs K 82 , Jukkola-Vuorinen A 83 , Kauppila S 84 , Andrulis IL 85 , Knight JA 86 , Glendon G 87 , Tchatchou S 88 , Devilee P 89 , Tollenaar RA 90 , Seynaeve C 91 , Van Asperen CJ 92 , García-Closas M 93 , Figueroa J 94 , Lissowska J 95 , Brinton L 94 , Czene K 96 , Darabi H 96 , Eriksson M 96 , Brand JS 96 , Hooning MJ 91 , Hollestelle A 91 , Van Den Ouweland AM 97 , Jager A 91 , Li J 98 , Liu J 99 , Humphreys K 96 , Shu XO 81 , Lu W 98 , Gao YT 100 , Cai H 81 , Cross SS 101 , Reed MW 102 , Blot W 103 , Signorello LB 103 , Cai Q 81 , Pharoah PD 104 , Perkins B 105 , Shah M 105 , Blows FM 105 , Kang D 106 , Yoo KY 107 , Noh DY 108 , Hartman M 109 , Miao H 110 , Chia KS 110 , Putti TC 111 , Hamann U 112 , Luccarini C 105 , Baynes C 105 , Ahmed S 105 , Maranian M 105 , Healey CS 105 , Jakubowska A 113 , Lubinski J 113 , Jaworska-Bieniek K 113 , Durda K 113 , Sangrajrang S 114 , Gaborieau V 115 , Brennan P 115 , Mckay J 115 , Slager S 69 , Toland AE 116 , Yannoukakos D 117 , Shen CY 118 , Hsiung CN 119 , Wu PE 120 , Ding SL 121 , Ashworth A 122 , Jones M 123 , Orr N 124 , Swerdlow AJ 125 , Tsimiklis H 126 , Makalic E 127 , Schmidt DF 127 , Bui QM 127 , Chanock SJ 94 , Hunter DJ 128 , Hein R 129 , Dahmen N 130 , Beckmann L 131 , Aaltonen K 44 , Muranen TA 44 , Heikkinen T 44 , Irwanto A 99 , Rahman N 123 , Turnbull CA 123 , Breast and Ovarian Cancer Susceptibility (BOCS) Study , Waisfisz Q 132 , Meijers-Heijboer HE 132 , Adank MA 132 , Van Der Luijt RB 133 , Hall P 96 , Chenevix-Trench G 4 , Dunning A 105 , Easton DF 104 , Cox A 134

Affiliations 

  • 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
Hum Mol Genet, 2015 Jan 01;24(1):285-98.
PMID: 25168388 DOI: 10.1093/hmg/ddu431

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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