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7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium
  1. Roger L Milne1,
  2. Justo Lorenzo-Bermejo2,3,
  3. Barbara Burwinkel4,5,
  4. Núria Malats1,
  5. Jose Ignacio Arias6,
  6. M Pilar Zamora7,
  7. Javier Benítez8,
  8. Manjeet K Humphreys9,
  9. Montserrat García-Closas10,11,
  10. Stephen J Chanock10,
  11. Jolanta Lissowska12,
  12. Mark E Sherman10,
  13. Arto Mannermaa13,14,
  14. Vesa Kataja15,16,
  15. Veli-Matti Kosma13,14,
  16. Heli Nevanlinna17,
  17. Tuomas Heikkinen17,
  18. Kristiina Aittomäki18,
  19. Carl Blomqvist19,
  20. Hoda Anton-Culver20,
  21. Argyrios Ziogas20,
  22. Peter Devilee21,22,
  23. Christie J van Asperen23,
  24. Rob A E M Tollenaar24,
  25. Caroline Seynaeve25,
  26. Per Hall26,
  27. Kamila Czene26,
  28. Jianjun Liu27,
  29. Astrid K Irwanto27,
  30. Daehee Kang28,
  31. Keun-Young Yoo28,
  32. Dong-Young Noh28,
  33. Fergus J Couch29,
  34. Janet E Olson30,
  35. Xianshu Wang29,
  36. Zachary Fredericksen30,
  37. Børge G Nordestgaard31,32,
  38. Stig E Bojesen31,32,
  39. Henrik Flyger33,
  40. Sara Margolin34,
  41. Annika Lindblom35,
  42. Peter A Fasching36,37,
  43. Ruediger Schulz-Wendtland38,
  44. Arif B Ekici39,
  45. Matthias W Beckmann36,
  46. Shan Wang-Gohrke40,
  47. Chen-Yang Shen41,42,
  48. Jyh-Cherng Yu43,
  49. Huan-Ming Hsu43,
  50. Pei-Ei Wu41,42,
  51. Graham G Giles44,
  52. Gianluca Severi44,
  53. Laura Baglietto44,
  54. Dallas R English45,
  55. Angela Cox46,
  56. Ian Brock46,
  57. Graeme Elliott46,
  58. Malcolm W R Reed47,
  59. Jonathan Beesley48,
  60. Xiaoqing Chen48,
  61. kConFab Investigators49,
  62. AOCS Group48,49,
  63. Olivia Fletcher50,
  64. Lorna Gibson51,
  65. Isabel dos Santos Silva51,
  66. Julian Peto51,
  67. Bernd Frank4,52,
  68. Joerg Heil5,
  69. Alfons Meindl53,
  70. Jenny Chang-Claude54,
  71. Rebecca Hein54,
  72. Alina Vrieling54,
  73. Dieter Flesch-Janys55,56,
  74. Melissa C Southey57,
  75. Letitia Smith57,
  76. Carmel Apicella45,
  77. John L Hopper45,
  78. Alison M Dunning58,
  79. Karen A Pooley58,
  80. Paul D P Pharoah9,58,
  81. Ute Hamann59,
  82. Beate Pesch60,
  83. Yon-Dschun Ko61,
  84. The GENICA Network59,60,61,62,63,64,
  85. Douglas F Easton9,
  86. Georgia Chenevix-Trench48
  1. 1Genetic and Molecular Epidemiology Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  2. 2Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
  3. 3Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  4. 4Molecular Epidemiology Group, DKFZ, Heidelberg, Germany
  5. 5Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany
  6. 6Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain
  7. 7Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain
  8. 8Human Genetics Group, Human Cancer Genetics Program, CNIO, Madrid, Spain
  9. 9Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  10. 10Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
  11. 11Sections of Epidemiology and Genetics, Institute of Cancer Research and Breakthrough Breast Cancer Research Centre, London, UK
  12. 12Department of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  13. 13School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Biocenter Kuopio, Kuopio, Finland
  14. 14Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
  15. 15Department of Oncology, Kuopio University Hospital, Kuopio, Finland
  16. 16School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland
  17. 17Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland
  18. 18Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland
  19. 19Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
  20. 20Department of Epidemiology, University of California Irvine, Irvine, California, USA
  21. 21Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  22. 22Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
  23. 23Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  24. 24Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands
  25. 25Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
  26. 26Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  27. 27Human Genetics Laboratory, Genome Institute of Singapore, Singapore
  28. 28Seoul National University College of Medicine, Seoul, Korea
  29. 29Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  30. 30Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  31. 31Copenhagen General Population Study, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark
  32. 32Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark
  33. 33Department of Breast Surgery (HF), Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark
  34. 34Department of Oncology–Pathology, Karolinska Institute, Stockholm, Sweden
  35. 35Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  36. 36Department of Gynecology and Obstetrics, University Breast Center, University Hospital Erlangen, Erlangen, Germany
  37. 37Department of Medicine Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
  38. 38Institute of Diagnostic Radiology, University Hospital Erlangen, Erlangen, Germany
  39. 39Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
  40. 40Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany
  41. 41Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  42. 42Taiwan Biobank, Taipei, Taiwan
  43. 43Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan
  44. 44Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
  45. 45Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia
  46. 46Institute for Cancer Studies, Sheffield University Medical School, Sheffield, UK
  47. 47Academic Unit of Surgical Oncology, Sheffield University Medical School, Sheffield, UK
  48. 48Queensland Institute of Medical Research, Brisbane, Australia
  49. 49Peter MacCallum Cancer Centre, Melbourne, Australia
  50. 50Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
  51. 51London School of Hygiene and Tropical Medicine, London, UK
  52. 52Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany
  53. 53Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany
  54. 54Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany
  55. 55Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany
  56. 56Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany
  57. 57Department of Pathology, The University of Melbourne, Melbourne, Australia
  58. 58Department of Oncology, University of Cambridge, Cambridge, UK
  59. 59Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany
  60. 60Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany
  61. 61Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
  62. 62Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
  63. 63University of Tübingen, Tübingen, Germany
  64. 64Institute of Pathology, University of Bonn, Bonn, Germany
  1. Correspondence to Dr Roger L Milne, Genetic and Molecular Epidemiology Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Calle Melchor Fernández Almagro, 3, 28039 Madrid, Spain; rmilne{at}cnio.es

Abstract

Background Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies.

Methods The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression.

Results For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p=0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p=0.001). The OR was greater at younger ages (p trend=0.01).

Conclusion This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.

  • Breast neoplasms
  • molecular epidemiology
  • genetic predisposition to disease
  • epidemiology
  • genetic epidemiology
  • cancer: breast
  • other oncology

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Footnotes

  • Competing interests None.

  • Ethics approval Ethics approval was provided by the relevant local institutional review boards for each of the 23 studies that contributed data.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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