Research article
Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
1 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK
2 Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC Canada
3 Genetics and Population Health Division, Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia
4 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France and INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France
5 Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Via Roma 57, 56125 Pisa, Italy
6 Department of Oncology, Lund University Hospital, Lund, Sweden
7 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
8 Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
9 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
10 Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
11 Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
12 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
13 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin and Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland
14 Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain and Spanish Network on Rare Diseases (CIBERER)
15 Institute of Biology and Molecular Genetics. Universidad de Valladolid (IBGM-UVA), Valladolid, Spain
16 Oncology unit. Hospital clinico Universitario "Lozano Blesa", Zaragoza, Spain
17 Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain and Spanish Network on Rare Diseases (CIBERER)
18 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
19 Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands
20 Department of Clinical Genetics, Academic Meical Center, Amsterdam, The Netherlands
21 Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands
22 Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands
23 Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands
24 Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands
25 Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
26 Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
27 Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
28 Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands
29 Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands
30 Netherlands Cancer Institute, Amsterdam, The Netherlands
31 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
32 Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK
33 Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK
34 Yorkshire Regional Genetics Service, Leeds, UK
35 Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK
36 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK
37 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK
38 Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, UK
39 Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
40 Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK
41 Medical Genetics Unit, St George's, University of London, UK
42 Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, and Department of Medical Genetics, Queens University Belfast, Belfast UK
43 Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK
44 All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK
45 Clinical Genetics Department, St Michael's Hospital, Bristol, UK
46 North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK
47 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
48 Clinical Molecular Genetics Laboratory, Fox Chase Cancer Center, Philadelphia, PA, USA
49 Service de Génétique Oncologique, Institut Curie, Paris, France, Unité INSERM U830, Institut Curie, Paris, France, Université Paris Descartes, Faculté de Médecine, Paris, France
50 Service de Génétique Oncologique, Institut Curie, Paris, France and Université Paris Descartes, Faculté de Pharmacie, Paris, France
51 Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, Paris, France
52 Service de Génétique Oncologique, Institut Curie, Paris, France
53 INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France
54 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France
55 Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France and INSERM U946, Fondation Jean Dausset, Paris, France
56 Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France
57 Département Oncologie génétique, Prévention et Dépistage, INSERM CIC-P9502, Institut Paoli-Calmettes/Université d'Aix-Marseille II, Marseille, France
58 Centre Antoine Lacassagne, Nice, France
59 Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France
60 Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, BP 1125 Chambéry, France
61 Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France
62 Cancer Genetics Network "Groupe Génétique et Cancer", Fédération Nationale des Centres de Lutte Contre le Cancer, France
63 Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
64 Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
65 Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Surgery, Harvard Medical School, 27 Drydock Avenue, Boston, MA 02210, USA
66 Department of Epidemiology, Columbia University, New York, NY, USA
67 Centre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Melbourne School of Population Health, Level 1, 723 Swanston Street, The University of Melbourne, VIC 3010, Australia
68 Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538, USA
69 Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Australia
70 Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, SOM 4B454, Salt Lake City, UT 84132, USA
71 Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
72 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
73 Department of Pathology, Landspitali - University Hospital, Reykjavik Iceland and Faculty of Medicine, University of Iceland, Reykjavik, Iceland
74 Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
75 Department of Environmental Medicine, NYU Cancer Institute, New York University School of Medicine, New York, NY, USA
76 Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY, USA
77 Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA
78 Australia New Zealand (ANZGOG), Westmead Hospital, Sydney, Australia
79 Ohio State University, Columbus Cancer Council, Columbus, OH, USA
80 Evanston CCOP - NorthShore University Health System; University of Chicago, Chicago, IL, USA
81 Southern Pines Women's Health Center, P.C., University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
82 Sarasota Memorial Healthcare, Tufts Medical Center, Sarasota, Florida, USA
83 Department of Molecular Virology, Immunology and Medical Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
84 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy
85 U.O.C. di Oncologia, ULSS5 Ovest Vicentino, Italy
86 Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
87 Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA
88 Latvian Biomedical Research and Study Centre, Latvia
89 Genetic Counselling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain
90 Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain
91 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
92 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
93 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los Angeles, CA, USA
94 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
95 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Malaysia and University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
96 Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA
97 UCSF Cancer Risk Program, University of California, San Francisco, CA; UCSF Departments of Medicine, Epidemiology, and Biostatistics, Sand Francisco, CA, USA
98 Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, South Africa
99 Oncogenetics Laboratory. Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital. Barcelona, Spain
100 The Hong Kong Hereditary Breast Cancer Family Registry; The Universtiy of Hong Kong; Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong
101 Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University hospital of Cologne, Cologne, Germany
102 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
103 Department of Gynaecology and Obstetrics, Division of Tumour Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
104 Department of Gynaecology and Obstetrics, Ludwig-Maximilian University Munich, Munich, Germany
105 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
106 Institute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
107 Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
108 Institute of Human Genetics, University of Münster, Münster, Germany
109 Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
110 Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany
111 Department of Gynaecology and Obstetrics, University Hospital Ulm, Germany
112 Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany
113 Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Germany
114 Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University. Dresden, Germany
115 Institute of Human Genetics, University Regensburg, Regensbirg. Germany
116 Institute of Human Genetics, University Hospital Frankfurt a.M., Germany Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain
117 Molecular Oncology Laboratory, Hospital Clinico San Carlos, Martin Lagos s/n, Madrid, Spain
118 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, P.O. BOX 700, 00029 HUS, Helsinki, Finland
119 Faculty of Medicine - Medicine and Medical Specialties, Université de Montréal Hemato-oncology service, Hôpital du Sacré-Coeur de Montréal, 5400 Gouin Blvd West Montreal, QC, Canada
120 Peter MacCallum Cancer Center, Melbourne, VIC, Australia
121 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
122 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
123 Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA
124 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
125 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Milan, Italy and IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
126 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Milan, Italy
127 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan Italy
128 Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy and Consortium for Genomics Technology (Cogentech), Milan, Italy
129 Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy
130 Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Firenze, Italy
131 Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
132 Clinical Genetics Branch, DCEG, NCI; Room EPS 7032, Rockville, MD 20852, USA
133 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada
134 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada
135 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
136 Ontario Cancer Genetics Network: Cancer Care Ontario, Toronto, ON, Canada
137 Department of Clinical Genetics, Odense University Hospital, Denmark
138 Department of Clincial Genetics, Rigshospital and Copenhagen University, Denmark
139 Department of Clinical Genetics, Skejby Hospital, Aarhus, Denmark
140 Department of Clinical Genetics, Vejle Hospital, Denmark
141 Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN, USA
142 Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City and Canada Research Chair in Oncogenetics, Department of Molecular Medicine, Faculty of Medicine, Laval University, QC, Canada
Breast Cancer Research 2012, 14:R33 doi:10.1186/bcr3121
Published: 20 February 2012Abstract
Introduction
Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Methods
To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Results
Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
Conclusions
The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
