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Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk

Guo X 1 , Long J 1 , Zeng C 1 , Michailidou K 2 , Ghoussaini M 3 , Bolla MK 2 Show all authors , Wang Q 2 , Milne RL 4 , Shu XO 1 , Cai Q 1 , Beesley J 5 , Kar SP 3 , Andrulis IL 6 , Anton-Culver H 7 , Arndt V 8 , Beckmann MW 9 , Beeghly-Fadiel A 1 , Benitez J 10 , Blot W 11 , Bogdanova N 12 , Bojesen SE 13 , Brauch H 14 , Brenner H 15 , Brinton L 16 , Broeks A 17 , Brüning T 18 , Burwinkel B 19 , Cai H 1 , Canisius S 17 , Chang-Claude J 20 , Choi JY 21 , Couch FJ 22 , Cox A 23 , Cross SS 24 , Czene K 25 , Darabi H 25 , Devilee P 26 , Droit A 27 , Dörk T 28 , Fasching PA 29 , Fletcher O 30 , Flyger H 31 , Fostira F 32 , Gaborieau V 33 , García-Closas M 34 , Giles GG 4 , Grip M 35 , Guénel P 36 , Haiman CA 37 , Hamann U 38 , Hartman M 39 , Hollestelle A 40 , Hopper JL 41 , Hsiung CN 42 , Ito H 43 , Jakubowska A 44 , Johnson N 30 , Kabisch M 38 , Kang D 45 , Khan S 46 , Knight JA 47 , Kosma VM 48 , Lambrechts D 49 , Le Marchand L 50 , Li J 25 , Lindblom A 51 , Lophatananon A 52 , Lubinski J 44 , Mannermaa A 48 , Manoukian S 53 , Margolin S 54 , Marme F 55 , Matsuo K 56 , McLean CA 57 , Meindl A 58 , Muir K 59 , Neuhausen SL 60 , Nevanlinna H 46 , Nord S 61 , Olson JE 62 , Orr N 63 , Peterlongo P 64 , Putti TC 65 , Rudolph A 20 , Sangrajrang S 66 , Sawyer EJ 67 , Schmidt MK 17 , Schmutzler RK 68 , Shen CY 69 , Shi J 1 , Shrubsole MJ 1 , Southey MC 70 , Swerdlow A 71 , Teo SH 72 , Thienpont B 49 , Toland AE 73 , Tollenaar RA 74 , Tomlinson IP 75 , Truong T 36 , Tseng CC 37 , van den Ouweland A 76 , Wen W 1 , Winqvist R 77 , Wu A 37 , Yip CH 78 , Zamora MP 79 , Zheng Y 80 , Hall P 25 , Pharoah PD 81 , Simard J 27 , Chenevix-Trench G 5 , kConFab Investigators , Dunning AM 3 , Easton DF 81 , Zheng W 82

Affiliations 

  • 1 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 2 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 3 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 4 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Victoria, Australia
  • 5 Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 6 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Canada
  • 7 Department of Epidemiology, University of California Irvine, Irvine, California
  • 8 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
  • 9 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  • 10 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain. Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
  • 11 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. International Epidemiology Institute, Rockville, Maryland
  • 12 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 13 Copenhagen General Population Study, Herlev Hospital, Herlev, Denmark. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 14 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. University of Tübingen, Tübingen, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany
  • 15 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 16 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
  • 17 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
  • 18 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Bochum, Germany
  • 19 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany
  • 20 Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
  • 21 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
  • 22 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 23 Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, United Kingdom
  • 24 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom
  • 25 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 26 Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
  • 27 Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec, Canada
  • 28 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 29 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany. David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, California
  • 30 Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom
  • 31 Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 32 Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece
  • 33 International Agency for Research on Cancer, Lyon, France
  • 34 Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom
  • 35 Department of Surgery, Oulu University Hospital and University of Oulu, Oulu, Finland
  • 36 Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France. University Paris-Sud, Villejuif, France
  • 37 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  • 38 Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany
  • 39 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. Department of Surgery, National University Health System, Singapore
  • 40 Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 41 Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Victoria, Australia
  • 42 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 43 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan
  • 44 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 45 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
  • 46 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
  • 47 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  • 48 School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
  • 49 Vesalius Research Center, Leuven, Belgium. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
  • 50 University of Hawaii Cancer Center, Honolulu, Hawaii
  • 51 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 52 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, United Kingdom
  • 53 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 54 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden
  • 55 National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  • 56 Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
  • 57 Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia
  • 58 Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany
  • 59 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy. Institute of Population Health, University of Manchester, Manchester, United Kingdom
  • 60 Beckman Research Institute of City of Hope, Duarte, California
  • 61 Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Ullernchausseen, Oslo, Norway. K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien, Oslo, Norway
  • 62 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 63 Division of Breast Cancer Research, Institute of Cancer Research, London, United Kingdom; Cancer Research, Institute of Cancer Research, London, United Kingdom
  • 64 IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
  • 65 Department of Pathology, National University Health System, Singapore
  • 66 National Cancer Institute, Bangkok, Thailand
  • 67 Research Oncology, Guy's Hospital, King's College London, London, United Kingdom
  • 68 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany. Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany. Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany. Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
  • 69 School of Public Health, China Medical University, Taichung, Taiwan. Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 70 Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  • 71 Division of Genetics and Epidemiology and Division of Breast Cancer Research, Institute of Cancer Research, London, United Kingdom
  • 72 Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia. Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 73 Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
  • 74 Department of Surgical Oncology, Leiden University Medical Center, Leiden, the Netherlands
  • 75 Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
  • 76 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 77 Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry, University of Oulu, Oulu, Finland. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  • 78 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 79 Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain
  • 80 Shanghai Municipal Center for Disease Control and Prevention, Shanghai, PR China
  • 81 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
  • 82 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. wei.zheng@vanderbilt.edu
Cancer Epidemiol Biomarkers Prev, 2015 Nov;24(11):1680-91.
PMID: 26354892 DOI: 10.1158/1055-9965.EPI-15-0363

Abstract

BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.

METHODS: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.

RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.

CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.

IMPACT: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

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

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