Letter abstract

Nature Genetics 41, 585 - 590 (2009)
Published online: 29 March 2009 | doi:10.1038/ng.354

Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

Shahana Ahmed1,87, Gilles Thomas2,87, Maya Ghoussaini1,87, Catherine S Healey1,87, Manjeet K Humphreys3,87, Radka Platte1, Jonathan Morrison3, Melanie Maranian1, Karen A Pooley3, Robert Luben4, Diana Eccles5, D Gareth Evans6, Olivia Fletcher7,8, Nichola Johnson7, Isabel dos Santos Silva8, Julian Peto8,9, Michael R Stratton10, Nazneen Rahman11, Kevin Jacobs2,12,13, Ross Prentice14, Garnet L Anderson14, Aleksandar Rajkovic15, J David Curb16, Regina G Ziegler2, Christine D Berg17, Saundra S Buys18, Catherine A McCarty19, Heather Spencer Feigelson20, Eugenia E Calle20, Michael J Thun20, W Ryan Diver20, Stig Bojesen21,22, Børge G Nordestgaard21,22, Henrik Flyger23, Thilo Dörk24, Peter Schürmann24, Peter Hillemanns24, Johann H Karstens25, Natalia V Bogdanova24,25,26, Natalia N Antonenkova26, Iosif V Zalutsky26, Marina Bermisheva24,27, Sardana Fedorova28, Elza Khusnutdinova27, SEARCH1,3, Daehee Kang29, Keun-Young Yoo29, Dong Young Noh29, Sei-Hyun Ahn29, Peter Devilee30,31, Christi J van Asperen32, R A E M Tollenaar33, Caroline Seynaeve34, Montserrat Garcia-Closas2, Jolanta Lissowska35, Louise Brinton36, Beata Peplonska37, Heli Nevanlinna38, Tuomas Heikkinen38, Kristiina Aittomäki39, Carl Blomqvist40, John L Hopper41, Melissa C Southey42, Letitia Smith43, Amanda B Spurdle43, Marjanka K Schmidt44, Annegien Broeks44, Richard R van Hien44, Sten Cornelissen44, Roger L Milne45, Gloria Ribas46, Anna González-Neira47, Javier Benitez46,47, Rita K Schmutzler48, Barbara Burwinkel49,50, Claus R Bartram51, Alfons Meindl52, Hiltrud Brauch53,54, Christina Justenhoven53,54, Ute Hamann55, The GENICA Consortium53,54, Jenny Chang-Claude56, Rebecca Hein56, Shan Wang-Gohrke57, Annika Lindblom58, Sara Margolin59, Arto Mannermaa60,61, Veli-Matti Kosma60,61, Vesa Kataja62,63, Janet E Olson64, Xianshu Wang64, Zachary Fredericksen64, Graham G Giles41,65, Gianluca Severi41,65, Laura Baglietto41,65, Dallas R English41,65, Susan E Hankinson66, David G Cox66, Peter Kraft67, Lars J Vatten68, Kristian Hveem68, Merethe Kumle69, Alice Sigurdson2, Michele Doody2, Parveen Bhatti2, Bruce H Alexander70, Maartje J Hooning71, Ans M W van den Ouweland72, Rogier A Oldenburg72, Mieke Schutte71, Per Hall73, Kamila Czene73, Jianjun Liu74, Yuqing Li74, Angela Cox75, Graeme Elliott75, Ian Brock75, Malcolm W R Reed76, Chen-Yang Shen77,78, Jyh-Cherng Yu79, Giu-Cheng Hsu79, Shou-Tung Chen80, Hoda Anton-Culver81, Argyrios Ziogas81, Irene L Andrulis82,83, Julia A Knight82, kConFab84, Australian Ovarian Cancer Study Group43,84, Jonathan Beesley43, Ellen L Goode64, Fergus Couch64, Georgia Chenevix-Trench43, Robert N Hoover2, Bruce A J Ponder1,85, David J Hunter66,67, Paul D P Pharoah1,3, Alison M Dunning1, Stephen J Chanock86 & Douglas F Easton3

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Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage1. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 times 10-23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 times 10-8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

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  1. Department of Oncology, University of Cambridge, Cambridge, UK.
  2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
  3. CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  4. EPIC, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  5. Wessex Clinical Genetics Service, Princess Ann Hospital, Southampton, UK.
  6. Regional Genetic Service, St. Mary's Hospital, Manchester, UK.
  7. Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
  8. London School of Hygiene and Tropical Medicine and Institute of Cancer Research, London, UK.
  9. Institute of Cancer Research, Sutton, Surrey, UK.
  10. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
  11. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.
  12. Bioinformed Consulting Services, Gaithersburg, Maryland, USA.
  13. Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland, USA.
  14. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  15. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.
  16. Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii/Pacific Health Research Institute, Honolulu, Hawaii, USA.
  17. Division of Cancer Prevention, NCI, NIH, DHHS, Bethesda, Maryland, USA.
  18. Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
  19. The Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
  20. Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia, USA.
  21. Department of Clinical Biochemistry, Copenhagen University Hospital, Herlev, Denmark
  22. Copenhagen General Population Study, Copenhagen University Hospital, Herlev, Denmark
  23. Department of Breast Surgery, Copenhagen University Hospital, Herlev, Denmark.
  24. Departments of Obstetrics and Gynaecology, and
  25. Radiation Oncology, Hannover Medical School, Hannover, Germany.
  26. N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
  27. Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
  28. Department of Medical Genetics, Yakut Research Center of Russian Academy of Medical Sciences, Yakutsk, Russia.
  29. Seoul National University College of Medicine, Seoul, Korea.
  30. Departments of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  31. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  32. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  33. Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
  34. Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
  35. Department of Epidemiology and Cancer Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland.
  36. Hormonal and Reproductive Epidemiology Branch, National Cancer Institute, Rockville, Maryland, USA.
  37. Department of Occupational & Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
  38. Departments of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland.
  39. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
  40. Departments of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
  41. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia.
  42. Department of Pathology, University of Melbourne, Melbourne, Australia.
  43. Queensland Institute for Medical Research, Brisbane, Australia.
  44. Netherlands Cancer Institute, Amsterdam, The Netherlands.
  45. Genetic and Molecular Epidemiology Group.
  46. Human Genetics Group.
  47. National Genotyping Centre (CEGEN), Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  48. Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Köln, Germany.
  49. Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  50. Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
  51. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
  52. Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany.
  53. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  54. University of Tuebingen, Tuebingen, Germany.
  55. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
  56. Division of Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany.
  57. Women's Hospital of University of Ulm, Ulm, Germany.
  58. Department of Molecular Medicine and Surgery, Karolinska Institutet, S17176 Stockholm, Sweden.
  59. Department of Oncology and Pathology, Karolinska Institutet, S17176 Stockholm, Sweden.
  60. Institute of Clinical Medicine, Pathology and Forensic Medicine and Biocenter Kuopio, University of Kuopio, Kuopio, Finland.
  61. Departments of Pathology, Kuopio University Hospital, Kuopio, Finland.
  62. Department of Oncology, Kuopio University Hospital, Kuopio, Finland.
  63. Department of Oncology, Vaasa Central Hospital, Vaasa, Finland.
  64. Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
  65. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
  66. Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  67. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
  68. Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway.
  69. Institute of Community Medicine, University of Tromso, Tromso, Norway.
  70. Division of Environmental Health Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
  71. Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
  72. Department of Clinical Genetics, Rotterdam Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
  73. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
  74. Population Genetics, Genome Institute of Singapore, Singapore.
  75. Institute for Cancer Studies, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, UK.
  76. Academic Unit of Surgical Oncology, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, UK.
  77. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  78. Graduate Institute of Environmental Science, China Medical University, Taichong, Taiwan.
  79. Tri-Service General Hospital, Taipei, Taiwan.
  80. Changhua Christian Hospital, Changhua, Taiwan.
  81. Department of Epidemiology, University of California Irvine, Irvine, California, USA.
  82. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
  83. Ontario Familial Breast Cancer Registry, Cancer Care Ontario, Toronto, Ontario, Canada.
  84. Peter MacCallum Cancer Center, Melbourne, Australia.
  85. Cancer Research UK Cambridge Cancer Research Institute, Cambridge, UK.
  86. Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland, USA.
  87. These authors contributed equally to this work.

Correspondence to: Douglas F Easton3 e-mail: douglas@srl.cam.ac.uk



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