Research article
Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2
1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada
2 Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK
4 Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
5 Faculty of Medicine, University of Southampton, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, SO16 6YD, UK
6 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland
7 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N Soto Street, Los Angeles, CA 90089-9237, USA
8 Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA
9 National Cancer Institute, Division of Cancer Epidemiology and Genetics, Hormonal and Reproductive Epidemiology Branch, 6120 Executive Blvd., Rockville, MD 20852, USA
10 Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia
11 Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Kerpener Str. 62, Cologne, 50931, Germany
12 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France
13 INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France
14 Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, Santariskiu st 2, LT-08661 Vilnius and State Research Institute Innovative Medicine Center, Zygimantu st. 9, LT-01102 Vilnius, Lithuania
15 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
16 Department of Oncology, Rigshospitalet Bldg. 4262, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
17 Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)
18 Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), C/Sanz y Forés, N° 3, Valladolid, 47003, Spain
19 Instituto de investigación sanitaria de Aragón (IIS), Hospital clinico Universitario "Lozano Blesa", San Juan Bosco 15, Zaragoza, 50009, Spain
20 Molecular Diagnostics Laboratory, IRRP, National Center for Scientific Research Demokritos, Patriarchou Gregoriou E' & Neapoleos Str, Ag. Paraskevi 15310, Athens, Greece
21 Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, C/Melchor Fernández Almagro 3, Madrid, 28029, Spain and the Spanish Network on Rare Diseases (CIBERER)
22 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, 20133 Milan, Italy; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello 16, 20139 Milan, Italy
23 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), via Giacomo Venezian 1, Milan, 20133, Italy
24 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, via Ripamonti 435, Milan, 20141, Italy
25 Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy
26 Department of Genetics, Biology and BiochemIstry, University of Turin, Turin, Italy
27 Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Firenze, Italy
28 Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
29 Division of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy
30 Department of Experimental Oncology, Istituto Europeo di Oncologia. Milan, Italy; Consortium for Genomics Technology (Cogentech), Milan, Italy
31 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
32 Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
33 Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands
34 Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
35 Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands
36 Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands
37 Department of Human Genetics 836, Radboud University Nijmegen Medical Centre, P.O. BOX 9101, 6500 HB Nijmegen, The Netherlands
38 Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
39 Department of Surgical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
40 Department of Medical Genetics, University Medical Center Utrecht, The Netherlands
41 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
42 Barts Cancer Institute, Queen Mary University of London, Centre for Tumour Biology, Charterhouse Square, London, UK
43 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
44 Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK
45 Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK
46 Yorkshire Regional Genetics Service, Leeds, UK
47 Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK
48 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK
49 Clinical Genetics Department, St Michael's Hospital, Bristol, UK
50 North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK
51 North of Scotland Regional Genetics Service, NHS Grampian and University of Aberdeen, Foresterhill, Aberdeen, UK
52 Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, UK
53 Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, UK
54 Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, UK
55 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK
56 All Wales Medical Genetics Service, Glan Clwyd Hospital, Rhyl, UK
57 All Wales Medical Genetics Services, Singleton Hospital, Swansea, UK
58 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
59 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
60 Department of Gynaecology and Obstetrics, Division of Tumour Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany
61 Department of Gynaecology and Obstetrics, Ludwig-Maximillians University, Munich, Germany
62 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein (UKSH), Campus Kiel, Christian-Albrechts University, Kiel, Germany
63 Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
64 Institute of Human Genetics, Department of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
65 Department of Gynaecology and Obstetrics, University Hospital, Ulm, Germany
66 Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
67 Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University, Dresden, Germany
68 Institute of Human Genetics, University of Münster, Münster, Germany
69 Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany
70 Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Germany
71 Institute of Human Genetics, University Regensburg, Germany
72 Institute of Human Genetics, University Leipzig, Germany
73 Institute of Human Genetics, University Hospital, Frankfurt a.M., Germany
74 Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, UK
75 Service de Génétique Oncologique, Institut Curie, Paris, France
76 Genetic Unit, Avicenne Hospital, Assitance Publique-Hôpitaux de Paris, Paris, France; Sud-Francilien Hospital, Evry-Corbeil, France; University Hospital, Clermont-Ferrand, France
77 Centre François Baclesse, Caen, France
78 Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France
79 Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France
80 Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France
81 Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France
82 Cancer Genetics Unit, INSERM U916, Institut Bergonié, Université de Bordeaux, Bordeaux, France
83 Unité INSERM U830, Institut Curie, Paris, France; Université Paris Descartes, Faculté de Médecine, Paris, France
84 Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA
85 Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain
86 Department of Clinical Genetics, Helsinki University Central Hospital, Meilahdentie 2, 00290 Helsinki, Finland
87 Hereditary Cancer Program, Institut Català d'Oncologia, Hospital Duran i Reynals - Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
88 Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
89 Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada
90 Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC, Canada; Canada Research Chair in Oncogenetics, Department of Molecular Medicine, Faculty of Medicine, Laval University, QC, Canada
91 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy
92 Department of Oncology and Surgical Sciences, University of Padua and Istituto Oncologico Veneto IOV - IRCCS, Via Gattamelata 64, 35128 Padua, Italy
93 Peter MacCallum Cancer Centre, Melbourne, VIC 3052, Australia
94 Department of Anatomical Pathology, Prince of Wales Hospital, Randwick, NSW 2031, Australia
95 Abramson Cancer Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
96 University of Chicago, Chicago, IL, USA
97 City of Hope Comprehensive Cancer Center and Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA
98 Departments of Medicine, and Preventive Medicine and Public Health, Creighton University, Omaha, NE, USA
99 Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, CA, USA
100 Department of Internal Medicine and Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX; USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
101 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
102 Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA
103 University of Delaware, Newark, DE, USA
104 Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
105 Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
106 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, US National Cancer Institute, Rockville, MD, USA
107 Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
108 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
109 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada
110 Cancer Care Ontario, ON, Canada
111 Departments of Molecular Virology, Immunology and Medical Genetics and Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
112 Clinical Genetics, Rigshospital, Copenhagen University, Copenhagen, Denmark
113 Clinical Genetics, Odense University Hospital, Odense, Denmark
114 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
115 Clinical Genetics, Vejle Hospital, Denmark
116 Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy
117 Department of Clinical Genetics, Lund University Hospital, Lund, Sweden
118 Oncological Centre, Lund University Hospital, Lund, Sweden
119 Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
120 Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
121 Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
122 Department of Population Sciences, the Beckman Research Institute of the City of Hope, Duarte, CA, USA
123 UCSF Cancer Risk Program and Departments of Medicine and Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA
124 Department of Oncology, University of Cambridge, Cambridge, UK
125 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
126 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
127 Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA
128 Fox Chase Cancer Center, Philadelphia, PA, USA
129 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
130 Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
131 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, VIC, Australia
132 Department of Epidemiology, Columbia University, New York, NY, USA
133 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
134 Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA
135 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada; Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada
136 Breast Cancer Family Registry
137 Cancer Genetics Network "Groupe Génétique et Cancer", Fédération Nationale des Centres de Lutte Contre le Cancer
138 Netherlands Cancer Institute, Amsterdam, The Netherlands
139 Ontario Cancer Genetics Network, Cancer Care Ontario, 620 University Avenue, Toronto, ON M5G 2L7, Canada
140 Karolinska Institute, Stockholm, Sweden
Breast Cancer Research 2011, 13:R110 doi:10.1186/bcr3052
Published: 2 November 2011Abstract
Introduction
Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.
Methods
We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.
Results
The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.
Conclusions
The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
