Letter | Published:

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer

Nature Genetics volume 43, pages 12101214 (2011) | Download Citation

Abstract

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

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Acknowledgements

This work was supported by a US Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C.A.H. (W81XWH-08-1-0383), the Norris Foundation, the Mayo Clinic College of Medicine, Komen Foundation for the Cure, the Breast Cancer Research Foundation and US National Institutes of Health grants CA128978, CA122340 and CA148065. Study specific acknowledgments are listed in the Supplementary Note.

Author information

Affiliations

  1. Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA.

    • Christopher A Haiman
    • , Gary K Chen
    • , Christopher K Edlund
    • , Andrea Holbrook
    • , Sue A Ingles
    • , Loreall C Pooler
    • , Fredrick Schumacher
    • , Xin Sheng
    • , David Van Den Berg
    • , Peggy Wan
    • , Lucy Y Xia
    • , Daniel O Stram
    •  & Brian E Henderson
  2. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Celine M Vachon
    • , Timothy Lesnick
    • , Curtis Olswold
    • , Kristen N Stevens
    • , Susan L Slager
    •  & Fergus J Couch
  3. Genomic Epidemiology Group, DKFZ, Heidelberg, Germany.

    • Federico Canzian
  4. Centre for Cancer Genetic Epidemiology, Strangeways Laboratory, Worts Causeway, Cambridge, UK.

    • Alison Dunning
    • , Shahana Ahmed
    • , Paul D P Pharoah
    •  & Douglas Easton
  5. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Robert C Millikan
    •  & Sarah Nyante
  6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Xianshu Wang
    •  & Fergus J Couch
  7. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Foluso Ademuyiwa
  8. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Christine B Ambrosone
  9. Cancer Epidemiology Centre, The Cancer Council Victoria & Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Victoria, Australia.

    • Laura Baglietto
    • , Graham G Giles
    •  & Gianluca Severi
  10. Department of Translational Oncology, Westmead Hospital, Western Sydney Local Health Network, Westmead, New South Wales, Australia.

    • Rosemary Balleine
  11. The Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.

    • Elisa V Bandera
  12. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

    • Matthias W Beckmann
    •  & Peter A Fasching
  13. Division of Cancer Prevention, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Christine D Berg
  14. Division of Cancer Etiology, Department of Population Science, Beckman Research Institute, City of Hope, California, USA.

    • Leslie Bernstein
  15. Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.

    • Carl Blomqvist
  16. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • William J Blot
    • , Sandra L Deming
    • , Lisa B Signorello
    •  & Wei Zheng
  17. International Epidemiology Institute, Rockville, Maryland, USA.

    • William J Blot
    •  & Lisa B Signorello
  18. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.

    • Hiltrud Brauch
  19. University of Tübingen, Tübingen, Germany.

    • Hiltrud Brauch
  20. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Julie E Buring
    •  & Daniel I Chasman
  21. Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Lisa A Carey
  22. Australian Breast Cancer Tissue Bank, University of Sydney at the Westmead Millennium Institute, Westmead, New South Wales, Australia.

    • Jane E Carpenter
    •  & Christine L Clarke
  23. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.

    • Jenny Chang-Claude
    • , Rebecca Hein
    •  & Stephan Nickels
  24. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Stephen J Chanock
    • , Robert N Hoover
    •  & Regina G Ziegler
  25. Institute for Cancer Studies, Department of Oncology, Faculty of Medicine, Dentistry & Health, University of Sheffield, Sheffield, UK.

    • Angela Cox
  26. Academic Unit of Pathology, Department of Neuroscience, Faculty of Medicine, Dentistry & Health, University of Sheffield, Sheffield, UK.

    • Simon S Cross
  27. Department of Pharmacology, Mayo Clinic, Rochester, Minnesota, USA.

    • Robert B Diasio
    •  & Adam M Lee
  28. Department of Clinical Therapeutics, “Alexandra” Hospital, University of Athens School of Medicine, Athens, Greece.

    • Athanasios M Dimopoulos
  29. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.

    • W Ryan Driver
  30. Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany.

    • Thomas Dünnebier
    •  & Ute Hamann
  31. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

    • Lorraine Durcan
    • , Diana Eccles
    • , Susan M Gerty
    • , Nikki Graham
    •  & William J Tapper
  32. Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

    • Arif B Ekici
  33. Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California, USA.

    • Peter A Fasching
  34. Kaiser Permanente Colorado, Denver, Colorado, USA.

    • Heather S Feigelson
  35. Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.

    • Dieter Flesch-Janys
    •  & Judith Heinz
  36. Molecular Diagnostics Laboratory Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research “Demokritos”, Athens, Greece.

    • Florentia Fostira
    • , Irene Konstantopoulou
    •  & Drakoulis Yannoukakos
  37. Division of Molecular Genetic Epidemiology, DKFZ, Heidelberg, Germany.

    • Asta Försti
  38. Center for Primary Health Care Research, University of Lund, Malmö, Sweden.

    • Asta Försti
  39. Department of Medical Oncology, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece.

    • George Fountzilas
  40. Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Lawrence, Kansas, USA.

    • Andrew K Godwin
  41. Washington University School of Medicine, Barnes-Jewish Hospital and Siteman Cancer Center, St. Louis, Missouri, USA.

    • Paul Goodfellow
    •  & Jennifer Ivanovich
  42. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.

    • Dario Greco
    •  & Heli Nevanlinna
  43. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Susan E Hankinson
  44. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Susan E Hankinson
    • , David J Hunter
    • , Sara Lindstrom
    •  & Peter Kraft
  45. Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.

    • Arndt Hartmann
    •  & Rüdiger Schulz-Wendtland
  46. Sylvester Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida, USA.

    • Jennifer J Hu
    •  & Jorge L Rodriguez-Gil
  47. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • David J Hunter
    • , Sara Lindstrom
    •  & Peter Kraft
  48. Human Genetics Division, Genome Institute of Singapore, Singapore.

    • Astrid Irwanto
    •  & Jianjun Liu
  49. Cancer Prevention Institute of California, Fremont, California.

    • Esther M John
  50. Stanford University School of Medicine and Stanford Cancer Center, Stanford, California, USA.

    • Esther M John
  51. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

    • Nicola Johnson
  52. Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.

    • Arja Jukkola-Vuorinen
  53. Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.

    • Rudolf Kaaks
  54. Department of Internal Medicine, Evangelische Kliniken Johanniter- und Waldkrankenhaus Bonn gGmbH, Bonn, Germany.

    • Yon-Dschun Ko
  55. Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, USA.

    • Laurence N Kolonel
    •  & Loïc Le Marchand
  56. Department of Pathology, Imaging Centre, Kuopio University Hospital, Kuopio, Finland.

    • Veli-Matti Kosma
  57. Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Swati Kulkarni
  58. Vesalius Research Center, Vlaams Instituut voor Biotechnologie, Leuven, Belgium.

    • Diether Lambrechts
    •  & Els Wauters
  59. Vesalius Research Center, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
    •  & Els Wauters
  60. Institute of Clinical Medicine, Department of Pathology, University of Eastern Finland Biocenter Kuopio, Kuopio, Finland.

    • Arto Mannermaa
  61. Department of Pathology, Imaging Centre, Kuopio University Hospital, Kuopio, Finland.

    • Arto Mannermaa
  62. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

    • Sara Margolin
  63. Queensland Institute of Medical Research (QIMR) Genome-Wide Association Study Collective, Brisbane, Queensland, Australia.

    • Nicholas G Martin
    •  & Grant W Montgomery
  64. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Penelope Miron
  65. Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA.

    • Julie Palmer
    •  & Lynn Rosenberg
  66. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Harsh Pathak
    •  & JoEllen Weaver
  67. Department of Internal Medicine, Oncology Section, “Hippokration” Hospital, Athens, Greece.

    • Dimitrios Pectasides
  68. Departments of Genetics and Pathology, Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina, USA.

    • Charles M Perou
  69. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Julian Peto
    •  & Isabel dos Santos Silva
  70. Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.

    • Michael F Press
  71. Laboratory of Cancer Genetics, Department of Clinical Genetics and Biocenter Oulu, University of Oulu, Oulu University Hospital, Oulu, Finland.

    • Katri Pylkäs
    •  & Robert Winqvist
  72. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Timothy R Rebbeck
  73. Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Eric Ross
  74. Institute of Pathology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.

    • Thomas Rüdiger
  75. National Institute for Health Research Comprehensive Biomedical Research Centre, Guy's & St. Thomas' National Health Service Foundation Trust, London, UK.

    • Elinor Sawyer
  76. Division of Experimental Therapy and Molecular Pathology and Division of Epidemiology, Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

    • Marjanka K Schmidt
  77. Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

    • Hans-Peter Sinn
  78. Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.

    • Melissa C Southey
  79. Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.

    • Ian Tomlinson
  80. Family Cancer Clinic, Netherlands Cancer Institut–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

    • Frans B L Hogervorst
  81. Multidisciplinary Breast Center, University Hospital Gasthuisberg, Leuven, Belgium.

    • Hans Wildiers
  82. Imperial College, London, UK.

    • Afshan Siddiq
  83. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft

Consortia

  1. The Gene Environment Interaction and Breast Cancer in Germany (GENICA) Consortium

    A full list of members is provided in the Supplementary Note.

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Contributions

Conceived of and designed the experiments: C.A.H. and F.J.C. Performed the experiments and analyzed the data: C.A.H., L.C.P., D.V.D.B., X.S., G.K.C., A. Holbrook, P.W., F.C., D.O.S., X.W., T.L., C.O., K.N.S., A.M.L., L.Y.X., S.L.S. and C.M.V. Contributed reagents, materials, analysis tools or comments on the manuscript: C.A.H., C.M.V., A.D., R.C.M., X.W., F.A., S.A., C.B.A., L. Baglietto, R.B., E.V.B., M.W.B., C.D.B., L. Bernstein, C.B., W.J.B., H.B., J.E.B., L.A.C., J.E.C., J.C.-C., S.J.C., D.I.C., C.L.C., A.C., S.S.C., S.L.D., R.B.D., A.M.D., W.R.D., T.D., L.D., D.E., C.K.E., A.B.E., P.A.F., H.S.F., D.F.-J., F.F., A.F., G.F., S.M.G., G.G.G., A.K.G., P.G., N.G., D.G., U.H., S.E.H., A. Hartmann, R.H., J.H., R.N.H., J.J.H., D.J.H., S.A.I., A.I., J.I., E.M.J., N.J., A.J.-V., R.K., Y.-D.K., L.N.K., I.K., V.-M.K., S.K., D.L., A.M.L., L.L.M., T.L., J.L., S.L., A.M., S.M., N.G.M., P.M., G.W.M., H.N., S. Nickels, S. Nyante, C.O., J. Palmer, H.P., D.P., C.M.P., J. Peto, P.D.P.P., L.C.P., M.F.P., K.P., T.R.R., J.L.R.-G., L.R., E.R., T.R., I.d.S.S., E.S., M.K.S., R.S.-W., F.S., G.S., X.S., L.B.S., H.-P.S., K.N.S., M.C.S., W.J.T., I.T., F.B.L.H., E.W., J.W., H.W., R.W., D.Y., W.Z., R.G.Z., A.S., S.L.S., D.O.S., D.E., P.K., B.E.H. and F.J.C. Wrote the paper: C.A.H. and F.J.C.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Christopher A Haiman or Fergus J Couch.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–4, Supplementary Figures 1 and 2 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.985

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