FP7 Outputs
Published June 21, 2016 | Version v1
Journal article Open

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Creators

  • 1. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA
  • 2. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 3. Proteomics Center, CHU de Québec Research Center and Department of Molecular Medicine, Laval University, Quebec, Canada
  • 4. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK
  • 5. Department of Surgery, St Vincent’s Hospital, Melbourne, VIC, Australia
  • 6. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia
  • 7. Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Padua, Italy
  • 8. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 9. Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 10. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada
  • 11. Department of Epidemiology, University of California Irvine, Irvine, CA, USA
  • 12. N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
  • 13. Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  • 14. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 15. University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 16. Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
  • 17. McGill University and Génome Québec Innovation Centre, Montréal, Canada
  • 18. Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 19. Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia
  • 20. Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 21. Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 22. Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 23. Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy
  • 24. Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
  • 25. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 26. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
  • 27. International Agency for Research on Cancer, Lyon, France
  • 28. Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • 29. Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany
  • 30. Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  • 31. Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
  • 32. Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
  • 33. Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
  • 34. Australian Breast Cancer Tissue Bank, Westmead Millennium Institute, University of Sydney, Sydney, Australia
  • 35. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 36. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea
  • 37. Center for Medical Genetics, Ghent University, Ghent, Belgium
  • 38. Westmead Millenium Institute for Medical Research, University of Sydney, Sydney, Australia
  • 39. Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK
  • 40. Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
  • 41. Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
  • 42. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  • 43. Oncogenetics Group, University Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO) and Universitat Autònoma de Barcelona, Barcelona, Spain
  • 44. Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • 45. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
  • 46. Department of Genetics, University of Pretoria, Pretoria, South Africa
  • 47. Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany
  • 48. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
  • 49. Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada
  • 50. Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK
  • 51. Institute of Human Genetics, Muenster, Germany
  • 52. Division of Population Sciences, Moffitt Cancer Center & Research Institute, Tampa, FL, USA
  • 53. Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
  • 54. Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 55. Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  • 56. Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 57. Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 58. ANZ GOTG Coordinating Centre, Australia New Zealand GOG, Camperdown, NSW, Australia
  • 59. Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel
  • 60. Section of Genetic Oncology, Deparment of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy
  • 61. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
  • 62. Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA
  • 63. Institute of Human Genetics, University Würzburg, Wurzburg, Germany
  • 64. INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France
  • 65. Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, 75248, Paris, France
  • 66. Department of Tumour Biology, Institut Curie, Paris, France
  • 67. GEMO study: National Cancer Genetics Network, UNICANCER Genetic Group, ᅟ, France
  • 68. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
  • 69. Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
  • 70. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
  • 71. Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France
  • 72. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 73. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
  • 74. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 75. Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 76. Cancer Center, Kuopio University Hospital, Kuopio, Finland
  • 77. Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • 78. Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia
  • 79. Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  • 80. Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands
  • 81. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating center: Netherlands Cancer Institute, Amsterdam, The Netherlands
  • 82. Suburban Hospital, Bethesda, MD, USA
  • 83. Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 84. Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA
  • 85. Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA
  • 86. N.N. Petrov Institute of Oncology, St. Petersburg, Russia
  • 87. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
  • 88. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan
  • 89. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 90. State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
  • 91. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, N, Denmark
  • 92. Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA
  • 93. Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC, Canada
  • 94. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 95. Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 96. Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland
  • 97. School of Medicine, National University of Ireland, Galway, Ireland
  • 98. Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 99. Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada
  • 100. Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research “Demokritos”, Athens, Greece
  • 101. The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China
  • 102. Vesalius Research Center, Leuven, Belgium
  • 103. Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
  • 104. University of Hawaii Cancer Center, Honolulu, HI, USA
  • 105. Department of Surgery, Soonchunhyang University and Hospital, Seoul, South Korea
  • 106. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 107. Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK
  • 108. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy
  • 109. Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden
  • 110. Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
  • 111. Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany
  • 112. Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
  • 113. Beckman Research Institute of City of Hope, Duarte, CA, USA
  • 114. Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
  • 115. Department of Medicine and Genetics, University of California, San Francisco, San Francisco, CA, USA
  • 116. Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  • 117. Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 118. Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, IL, USA
  • 119. Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
  • 120. Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
  • 121. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  • 122. University Hospital Gashuisberg, Leuven, Belgium
  • 123. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy
  • 124. IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy
  • 125. Department of Obstetrics and Gynecology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 126. Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
  • 127. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy
  • 128. Section of Cancer Genetics, The Institute of Cancer Research, London, UK
  • 129. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA
  • 130. Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa, Israel
  • 131. Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), Center for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Cologne, Germany
  • 132. Obstetrics and Gynecology, Ohio State University College of Medicine, Columbus, OH, USA
  • 133. National Cancer Institute, Bangkok, Thailand
  • 134. Research Oncology, Guy’s Hospital, King’s College London, London, UK
  • 135. Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany
  • 136. School of Public Health, China Medical University, Taichung, Taiwan
  • 137. Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 138. Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC, Canada
  • 139. Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, Australia
  • 140. Hannover Medical School, Hannover, Germany
  • 141. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • 142. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
  • 143. Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  • 144. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
  • 145. Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
  • 146. Department of Clinical Genetics, Odense University Hospital, Odense, C, Denmark
  • 147. Latvian Biomedical Research and Study Centre, Riga, Latvia
  • 148. Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, Canada
  • 149. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
  • 150. Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
  • 151. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 152. Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany
  • 153. Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA
  • 154. Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA
  • 155. Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland
  • 156. Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore
  • 157. Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
  • 158. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
  • 159. Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 160. Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia
  • 161. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Description

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.

Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.

Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.

Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

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Additional details

Funding

COGS – Collaborative Oncological Gene-environment Study 223175
European Commission