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      FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

      research-article
      1 , 2 , 1 , 3 , 1 , 4 , 5 , 5 , 5 , 3 , 3 , 3 , 6 , 7 , 8 , 9 , 5 , 10 , 11 , 12 , 13 , 14 , 14 , 12 , 15 , 16 , 17 , 17 , kConFab Investigators 18 , Australian Ovarian Cancer Study Group 18 19 , 20 , 21 , 21 , 22 , 23 , 24 , 25 , 26 , 26 , 27 , 28 , 28 , 27 , 28 , 29 , 30 , 30 , 30 , 31 , 32 , 33 , 33 , 32 , 34 , 35 , 36 , 37 , 38 , The GENICA Network 35 36 37 38 39 40 41 , 42 , 42 , 43 , 44 , 43 , 45 , 46 , 43 , 47 , 47 , 47 , 47 , 48 , 49 , 48 , 50 , 48 , 51 , 52 , 51 , 53 , 54 , 55 , 56 , 56 , 57 , 57 , 57 , 57 , 58 , 58 , 58 , 59 , 60 , 60 , 60 , 61 , 62 , 62 , 62 , 62 , 62 , 63 , 64 , 62 , 65 , 66 , 67 , 66 , 68 , 69 , 70 , 71 , 72 , TNBCC 73 , 74 , 75 , 75 , 76 , 76 , 77 , 78 , 77 , 79 , 80 , 81 , 80 , 81 , 80 , 81 , 82 , 83 , 84 , 85 , 84 , 85 , 86 , 87 , 88 , 87 , 88 , 87 , 89 , 90 , 91 , 92 , 91 , 93 , 94 , 90 , 91 , 92 , 90 , 91 , 92 , 95 , 95 , 96 , 96 , 97 , 97 , 97 , 98 , 99 , 71 , 100 , 100 , 100 , 30 , 101 , 30 , 101 , 30 , 101 , 57 , 57 , 57 , 102 , 103 , 103 , 104 , 105 , 106 , 107 , 107 , 108 , 109 , 110 , 111 , 112 , 13 , 113 , 114 , 113 , 115 , 113 , 116 , 116 , 116 , 116 , 112 , 112 , 117 , 118 , 119 , 120 , 120 , 120 , 120 , 121 , 121 , 122 , 123 , 124 , 125 , 124 , 116 , 19 , 3 , 42 , 3 , 42 , 126 , 127 , 1 , 5 , 1 , 30 , 101 , *
      British Journal of Cancer
      Nature Publishing Group
      breast cancer, SNP, FGF receptors, susceptibility, disease subtypes

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background:

          Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.

          Methods:

          Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.

          Results:

          Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.

          Conclusion:

          Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

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          Most cited references27

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          A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

          We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.
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            Genome-wide association study identifies five new breast cancer susceptibility loci.

            Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
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              Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

              Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                18 February 2014
                18 February 2014
                : 110
                : 4
                : 1088-1100
                Affiliations
                [1 ]Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO) , Madrid, Spain
                [2 ]Department of Molecular, Cellular and Developmental Biology, Yale University , New Haven, CT, USA
                [3 ]Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge , Cambridge, UK
                [4 ]Biostatistics Unit, IMDEA Food Institute , Madrid, Spain
                [5 ]Human Genotyping-CEGEN Unit, Spanish National Cancer Research Centre (CNIO) , Madrid, Spain
                [6 ]CRUK Cambridge Institute, University of Cambridge , Cambridge, UK
                [7 ]Hospital Monte Naranco , Oviedo, Spain
                [8 ]Department of Pathology, Hospital Universitario La Paz, IdiPAZ (Hospital La Paz Institute for Health Research) Universidad Autonoma de Madrid , Madrid, Spain
                [9 ]Laboratory of Pathology and Oncology, Research Unit, Hospital Universitario La Paz, IdiPAZ , Madrid, Spain
                [10 ]Department of Molecular Medicine and Surgery, Karolinska Institutet , Stockholm, Sweden
                [11 ]Department of Oncology—Pathology, Karolinska Institutet , Stockholm, Sweden
                [12 ]Division of Genetics and Epidemiology, The Institute of Cancer Research , Sutton, UK
                [13 ]Division of Breast Cancer Research, The Institute of Cancer Research , London, UK
                [14 ]Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research , London, UK
                [15 ]Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences , Fukuoka, Japan
                [16 ]Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute , Nagoya, Japan
                [17 ]Department of Breast Oncology, Aichi Cancer Center Hospital , Nagoya, Japan
                [18 ]Peter MacCallum Cancer Centre , Melbourne, Victoria, Australia
                [19 ]QIMR Berghofer Institute of Medical Research , Brisbane, Queensland, Australia
                [20 ]Saw Swee Hock School of Public Health, Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System , Singapore, Singapore
                [21 ]Saw Swee Hock School of Public Health, National University of Singapore and National University Health System , Singapore, Singapore
                [22 ]Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System , Singapore, Singapore
                [23 ]Research Oncology, Division of Cancer Studies, Kings College London Guy's Hospital , London, UK
                [24 ]Wellcome Trust Centre for Human Genetics, University of Oxford , Oxford, UK
                [25 ]Oxford Biomedical Research Centre, University of Oxford , Oxford, UK
                [26 ]School of Medicine, Clinical Science Institute, National University of Ireland , Galway, UK
                [27 ]Department of Preventive Medicine, Seoul National University College of Medicine , Seoul, Korea
                [28 ]Department of Biomedical Sciences, Seoul National University Graduate School , Seoul, Korea
                [29 ]Department of Surgery, Seoul National University College of Medicine , Seoul, Korea
                [30 ]Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne , Melbourne, Victoria, Australia
                [31 ]Department of Pathology, University of Melbourne , Melbourne, Victoria, Australia
                [32 ]Cancer Research Initiatives Foundation, Sime Darby Medical Centre , Subang Jaya, Malaysia
                [33 ]Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre , Kuala Lumpur, Malaysia
                [34 ]Singapore Eye Research Institute, National University of Singapore , Singapore
                [35 ]Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology , Stuttgart, Germany
                [36 ]University of Tübingen , Germany
                [37 ]Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA) , Germany
                [38 ]Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg , Germany
                [39 ]Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf , Germany
                [40 ]Institute of Pathology, Medical Faculty of the University of Bonn , Germany
                [41 ]Department of Internal Medicine, Evangelische Kliniken Bonn GmbH, Johanniter Krankenhaus, Bonn , Germany
                [42 ]Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge , Cambridge, UK
                [43 ]Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto, Ontario, Canada
                [44 ]Department of Molecular Genetics, University of Toronto , Toronto, Ontario, Canada
                [45 ]Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto , Toronto, Ontario, Canada
                [46 ]Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute , Toronto, Ontario, Canada
                [47 ]Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital , Amsterdam, The Netherlands
                [48 ]Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN , Erlangen, Germany
                [49 ]David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles , CA, USA
                [50 ]Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg , Erlangen, Germany
                [51 ]Institute of Biomedical Sciences, Academia Sinica , Taipei, Taiwan
                [52 ]College of Public Health, China Medical University , Taichong, Taiwan
                [53 ]Tri-Service General Hospital , Taipei, Taiwan
                [54 ]Cancer Center, Kaohsiung Medical University Chung-Ho Memorial Hospital , Kaohsiung, Taiwan
                [55 ]Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital , Kaohsiung, Taiwan
                [56 ]Department of Medicine, Vanderbilt University , Nashville, TN USA
                [57 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA
                [58 ]CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield , Sheffield, UK
                [59 ]Institute of Population Health, University of Manchester , Manchester, UK
                [60 ]Division of Health Sciences, Warwick Medical School , Coventry, UK
                [61 ]Ministry of Public Health , Bangkok, Thailand
                [62 ]Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center , Nashville, TN, USA
                [63 ]Shanghai Center for Disease Control and Prevention , Shanghai, China
                [64 ]Shanghai Cancer Institute , Shanghai, China
                [65 ]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
                [66 ]IFOM, Fondazione Istituto FIRC di Oncologia Molecolare , Milan, Italy
                [67 ]Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT) , Milan, Italy
                [68 ]Cogentech Cancer Genetic Test Laboratory , Milan, Italy
                [69 ]National Cancer Institute , Bangkok, Thailand
                [70 ]Genetic Susceptibility Group, International Agency for Research on Cancer , Lyon, France
                [71 ]Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, MN, USA
                [72 ]Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University , Columbus, OH, USA
                [73 ]Mayo Clinic , Rochester, MN, USA
                [74 ]Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos" , Athens, Greece
                [75 ]Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research , London, UK
                [76 ]London School of Hygiene and Tropical Medicine , London, UK
                [77 ]Department of Obstetrics and Gynecology, University of Heidelberg , Heidelberg, Germany
                [78 ]National Center for Tumor Diseases, University of Heidelberg , Heidelberg, Germany
                [79 ]Molecular Epidemiology Group, German Cancer Research Center (DKFZ) , Heidelberg, Germany
                [80 ]Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer , Villejuif, France
                [81 ]University Paris-Sud, UMRS 1018 , Villejuif, France
                [82 ]Inserm (National Institute of Health and Medical Research) , U775 Paris, France
                [83 ]Centre de Ressources Biologiques EPIGENETEC , Paris, France
                [84 ]Copenhagen General Population Study, Herlev University Hospital, University of Copenhagen , Copenhagen, Denmark
                [85 ]Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen , Copenhagen, Denmark
                [86 ]Department of Breast Surgery, Herlev University Hospital, University of Copenhagen , Copenhagen, Denmark
                [87 ]Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ) , Heidelberg, Germany
                [88 ]German Cancer Consortium (DKTK) , Heidelberg, Germany
                [89 ]Saarland Cancer Registry , Saarbrücken, Germany
                [90 ]School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland , Kuopio, Finland
                [91 ]Biocenter Kuopio, University of Eastern Finland , Kuopio, Finland
                [92 ]Department of Clinical Pathology, Kuopio University Hospital , Kuopio, Finland
                [93 ]School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland , Kuopio, Finland
                [94 ]Cancer Center, Kuopio University Hospital , Kuopio, Finland
                [95 ]Vesalius Research Center (VRC), VIB , Leuven, Belgium
                [96 ]Multidisciplinary Breast Center, University Hospital Gasthuisberg , Leuven, Belgium
                [97 ]Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) , Heidelberg, Germany
                [98 ]Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf , Hamburg, Germany
                [99 ]Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf , Hamburg, Germany
                [100 ]Department of Health Sciences Research, Mayo Clinic , Rochester, MN, USA
                [101 ]Cancer Epidemiology Centre, Cancer Council Victoria , Melbourne, Australia
                [102 ]University of Hawaii Cancer Center , Honolulu, HI, USA
                [103 ]Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Quebec Research Center and Laval University , Quebec, Canada
                [104 ]Department of Medicine, McGill University, Montreal , Montreal, Quebec, Canada
                [105 ]Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital , Montreal, Quebec, Canada
                [106 ]Département de médecine sociale et préventive, Département de santé environnementale et santé au travail, Université de Montréal , Montreal, Quebec, Canada
                [107 ]Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu University Hospital , Oulu, Finland
                [108 ]Department of Oncology, Oulu University Hospital, University of Oulu , Oulu, Finland
                [109 ]Department of Surgery, Oulu University Hospital, University of Oulu , Oulu, Finland
                [110 ]Department of Human Genetics, Leiden University Medical Center , Leiden, The Netherlands
                [111 ]Department of Surgical Oncology, Leiden University Medical Center , Leiden, The Netherlands
                [112 ]Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Centre , Rotterdam, The Netherlands
                [113 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute , Rockville, MD, USA
                [114 ]Division of Genetics and Epidemiology, Institute of Cancer Research and Breakthrough Breast Cancer Research Centre , London, UK
                [115 ]Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology , Warsaw, Poland
                [116 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , Stockholm, Sweden
                [117 ]Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center , Rotterdam, The Netherlands
                [118 ]Department of Surgical Oncology, Family Cancer Clinic, Erasmus University Medical Centre , Rotterdam, The Netherlands
                [119 ]Human Genetics Division, Genome Institute of Singapore , Singapore, Singapore
                [120 ]Department of Genetics and Pathology, Pomeranian Medical University , Szczecin, Poland
                [121 ]Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland
                [122 ]Department of Clinical Genetics, Helsinki University Central Hospital , Helsinki, Finland
                [123 ]Department of Oncology, Helsinki University Central Hospital , Helsinki, Finland
                [124 ]Department of Obstetrics and Gynaecology, Hannover Medical School , Hannover, Germany
                [125 ]Department of Radiation Oncology, Hannover Medical School , Hannover, Germany
                [126 ]Servicio de Cirugía General y Especialidades, Hospital Monte Naranco , Oviedo, Spain
                [127 ]Servicio de Oncología Médica, Hospital Universitario La Paz , Madrid, Spain
                Author notes
                Article
                bjc2013769
                10.1038/bjc.2013.769
                3929867
                24548884
                b33978f0-9263-486d-9a64-e4152d14a55a
                Copyright © 2014 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 04 September 2013
                : 08 November 2013
                : 15 November 2013
                Categories
                Genetics and Genomics

                Oncology & Radiotherapy
                breast cancer,snp,fgf receptors,susceptibility,disease subtypes
                Oncology & Radiotherapy
                breast cancer, snp, fgf receptors, susceptibility, disease subtypes

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