Full Paper

British Journal of Cancer advance online publication 17 November 2009; doi: 10.1038/sj.bjc.6605416

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deis zligler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMBA

  1. 1Human Genetics Group, Spanish National Cancer Research Centre, Madrid, Spain
  2. 2Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain
  3. 3Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain
  4. 4Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
  5. 5Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
  6. 6Department of Obstetrics and Gynaecology, Helsinki University Central Hospital (HUCH), HelsVinki, Finland
  7. 7Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Québec, Canada
  8. 8Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia
  9. 9Research Division, Peter MacCallum Cancer Center, Melbourne, Australia
  10. 10Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, CA, USA
  11. 11Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  12. 12Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
  13. 13Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA
  14. 14Istituto Europeo di Oncologia, Milan, Italy
  15. 15Centro di Riferimento Oncologico, IRCCS, Aviano, PN, Italy
  16. 16Cogentech, Consortium for Genomic Technologies, Milan, Italy
  17. 17Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
  18. 18Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  19. 19Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
  20. 20Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  21. 21Clinical Genetics Branch, National Cancer Institute, Rockville, MD, USA
  22. 22CHS National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
  23. 23Ontario Cancer Genetics Network (OCGN), Cancer Care Ontario, Toronto, ON, Canada
  24. 24Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai, Toronto, ON, Canada
  25. 25Clinical Genetics BFG, Odense University Hospital, Odense, Denmark
  26. 26Department of Clinical Genetics, Vejle Hospital, Vijle, Denmark
  27. 27Division of Pathology, Department of Oncology, University and University Hospital of Pisa, Pisa, Italy
  28. 28Sheba Medical Centre (SMC), Tel Hashomer, Israel
  29. 29The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  30. 30Rambam Medical Centre, Haifa, Israel
  31. 31Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
  32. 32Rambam Health Care Campus, Institute of Human Genetics, Haifa, Israel
  33. 33Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden
  34. 34Department of Oncology, University Hospital, Linköping, Sweden
  35. 35Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
  36. 36Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
  37. 37See acknowledgements
  38. 38Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
  39. 39Programa de Consejo Genético en Cáncer, Instituto Catalán de Oncología, Hospital Dr Josep Trueta-IdiBGi, Gerona, Spain
  40. 40Servicio de Oncología Médica del Hospital de la Santa Creu i Sant Pau, Barcelona, España
  41. 41IRRP, National Centre for Scientific Research 'Demokritos', Molecular Diagnostics Laboratory, Athens, Greece
  42. 42Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
  43. 43Department of Clinical Molecular Genetics, Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, NL, USA
  44. 44Department of Genetics and Cell Biology, University Medical Centre, Maastricht, NL
  45. 45Research Institute Growth and Development (GROW), Maastricht, NL, USA
  46. 46Department Clinical Molecular Genetics, Leiden University Medical Center, Leiden, NL, USA
  47. 47Department of Human Genetic, Leiden University Medical Center, Leiden, NL, USA
  48. 48Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, NL, USA
  49. 49Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, UK
  50. 50Department of Oncology, University of Cambridge, Cambridge, UK
  51. 51Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK
  52. 52Translational Cancer Genetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK
  53. 53Clinical Genetics, Guy's Hospital, London, UK
  54. 54Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK
  55. 55Department of Cancer Genetics, St Georges Hospital, University of London, London, UK
  56. 56Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK
  57. 57Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
  58. 58Fox Chase Cancer Center, Philadelphia, PA, USA
  59. 59Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France
  60. 60Laboratoire de Génétique Moléculaire, Signalisation et Cancer, UMR5201 CNRS, Université de Lyon, Lyon, France
  61. 61INSERM U509, Service de Génétique Oncologique, Institut Curie, Université Paris-Descartes, Paris, France
  62. 62Centre de Génétique, Dijon, France
  63. 63CLCC Georges François Leclerc, Dijon, France
  64. 64Human Molecular Oncology Laboratory, Centre Oscar Lambret, Lille, France
  65. 65Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France
  66. 66Department of Preventive Medicine, Creighton University, Omaha, NE, USA
  67. 67Northern California Cancer Center, Fremont, CA, USA
  68. 68Huntsman Cancer Institute, Salt Lake City, UT, USA
  69. 69Fox Chase Cancer Center, Philadelphia, PA, USA
  70. 70University of Melbourne, Melbourne, Australia
  71. 71Columbia University New York, NY, USA
  72. 72Dana Farber Cancer Institute, Boston, MA, USA
  73. 73Department of Dermatology, University of Utah, Salt Lake City, UT, USA
  74. 74Division of Special Gynecology, Department of OB/GYN, Medical University of Vienna, Vienna, Austria
  75. 75Department of Biochemistry, Pharmacology, and Genetics, Odense University Hospital, Odense, Denmark
  76. 76Department of Oncology, Landspitali-University Hospital, Reykjavik, Iceland (OThJ)
  77. 77Department of Medicine, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  78. 78GOG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA
  79. 79NorthShore University Health System, Evanston Northwestern Healthcare, Evanston, IL, USA
  80. 80Tufts University, New England Medical Center, Boston, MA, USA
  81. 81University of North Carolina, Chapel Hill, NC, USA
  82. 82St Elizabeth Medical Center, Edgewood, KY, USA
  83. 83Yale University School of Medicine, New Haven, CT, USA
  84. 84New York University School of Medicine, New York, NY, USA
  85. 85Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OHIO, USA
  86. 86Instituto Oncologico Veneto – IRCCS, Padua, Italy
  87. 87Department of Oncology and Surgical Sciences, Padua, Italy
  88. 88N.N. Petrov Institute of Oncology, St-Petersburg, Russia
  89. 89Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy
  90. 90Division of Molecular Gynaeco-Oncology, Department of Obstetrics and Gynaecology, University of Cologne, Cologne, Germany
  91. 91Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany
  92. 92Department of Obstetrics and Gynaecology, Technical University Munich, Munich, Germany
  93. 93Department of Obstetrics and Gynaecology, Ludwig-Maximilian University Munich, Munich, Germany
  94. 94Department of Obstetrics and Gynaecology, University of Schleswig-Holstein, Campus Kiel, Germany
  95. 95Department of Obstetrics and Gynaecology, Molecular Genetics Laboratory, University of Duesseldorf, Dusseldorf, Germany
  96. 96Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany
  97. 97University of Regensburg, Institute of Human Genetics, Regensburg, Germany
  98. 98Institute of Human Genetics, Charité, Humboldt University, Berlin, Germany
  99. 99Institute of Human Genetics, University of Frankfurt, Frankfurt, Germany
  100. 100Institute of Human Genetics, University of Leipzig, Leipzig, Germany
  101. 101Hospital Clínico San Carlos, Madrid, Spain

Correspondence: Dr A Osorio, Human Genetics Group, Spanish National Cancer Centre (CNIO), C/Melchor Fernández Almagro 3, 28029 Madrid, Spain; E-mail: aosorio@cnio.es

Received 5 August 2009; Accepted 12 October 2009; Published online 17 November 2009.

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Abstract

Background:

  

In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.

Methods:

  

We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.

Results:

  

We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers.

Conclusion:

  

This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Keywords:

BRCA1, BRCA2, ERCC4, breast cancer