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Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study

Roger L Milne1*, Mia M Gaudet2, Amanda B Spurdle3, Peter A Fasching4, Fergus J Couch5, Javier Benítez6, José Ignacio Arias Pérez7, M Pilar Zamora8, Núria Malats1, Isabel dos Santos Silva9, Lorna J Gibson9, Olivia Fletcher10, Nichola Johnson10, Hoda Anton-Culver11, Argyrios Ziogas11, Jonine Figueroa12, Louise Brinton12, Mark E Sherman12, Jolanta Lissowska13, John L Hopper14, Gillian S Dite14, Carmel Apicella14, Melissa C Southey15, Alice J Sigurdson16, Martha S Linet16, Sara J Schonfeld16, D Michal Freedman16, Arto Mannermaa171819, Veli-Matti Kosma171819, Vesa Kataja2021, Päivi Auvinen20, Irene L Andrulis222324, Gord Glendon23, Julia A Knight2225, Nayana Weerasooriya23, Angela Cox26, Malcolm WR Reed27, Simon S Cross28, Alison M Dunning29, Shahana Ahmed29, Mitul Shah29, Hiltrud Brauch30, Yon-Dschun Ko31, Thomas Brüning32, GENICA Network3031323334, Diether Lambrechts35, Joke Reumers35, Ann Smeets36, Shan Wang-Gohrke37, Per Hall38, Kamila Czene38, Jianjun Liu39, Astrid K Irwanto39, Georgia Chenevix-Trench3, Helene Holland3, kConFab40, AOCS341, Graham G Giles144243, Laura Baglietto1442, Gianluca Severi1442, Stig E Bojensen44, Børge G Nordestgaard44, Henrik Flyger44, Esther M John4546, Dee W West4546, Alice S Whittemore46, Celine Vachon47, Janet E Olson47, Zachary Fredericksen47, Matthew Kosel47, Rebecca Hein48, Alina Vrieling48, Dieter Flesch-Janys49, Judith Heinz49, Matthias W Beckmann50, Katharina Heusinger50, Arif B Ekici51, Lothar Haeberle50, Manjeet K Humphreys52, Jonathan Morrison52, Doug F Easton52, Paul D Pharoah29, Montserrat García-Closas1229, Ellen L Goode47 and Jenny Chang-Claude48

Author Affiliations

1 Genetic and Molecular Epidemiology Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid, 28029, Spain

2 Departments of Epidemiology and Population Health & of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Ave., New York, NY 10461, USA

3 Queensland Institute of Medical Research, 300 Herston Road, Brisbane, 4006, Australia

4 Division of Hematology and Oncology, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90024, USA

5 Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA

6 Human Genetics Group, Human Cancer Genetics Programme, CNIO, Melchor Fernández Almagro 3, Madrid, 28029, Spain

7 Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Avda. Dres. Fernández-Vega 9, Oviedo, 33012, Spain

8 Servicio de Oncología Médica, Hospital Universitario La Paz, Paseo de la Castellana 261, Madrid, 28046, Spain

9 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St., London, WC1E 7HT, UK

10 Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulman Road, London, SW36JB, UK

11 Department of Epidemiology, School of Medicine, UC Irvine, 224 Irvine Hall, Irvine, CA 92697, USA

12 Division of Cancer Epidemiology and Genetics, Hormonal and Reproductive Epidemiology Branch, National Cancer Institute, 6120 Executive Blvd, Rockville, MD 20852, USA

13 Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology, ul Roentgena 5, Warsaw, 02 781, Poland

14 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Level 1, 723 Swanston Street, Melbourne, 3010, Australia

15 Department of Pathology, The University of Melbourne, 5th floor, West Wing, Medical Building 181, Melbourne, 3010, Australia

16 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Executive Plaza South, Room 7094, Bethesda, MD 20892, USA

17 Institute of Clinical Medicine, Department of Pathology, University of Eastern Finland, Yliopistonranta 1, Kuopio, 70210, Finland

18 Department of Pathology, Kuopio University Hospital, Harjulantie 1, Kuopio, 70210, Finland

19 Biocenter Kuopio, Yliopistonranta 1, Kuopio, 70211, Finland

20 Department of Oncology, Kuopio University Hospital, Harjulantie 1, Kuopio, 70210, Finland

21 Department of Oncology, Vaasa Central Hospital, Hietalahdenkatu 2-4, Vaasa, 65130, Finland

22 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Toronto, ON, M5G 1X5, Canada

23 Ontario Cancer Genetics Network, Cancer Care Ontario, 620 University Avenue, Toronto, ON M5G 2C1, Canada

24 Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada

25 Dalla Lana School of Public Health, University of Toronto, 155 College Street, Toronto, ON M5T 3M7, Canada

26 Institute for Cancer Studies, Department of Oncology, University of Sheffield Medical School, Western Bank, Sheffield, S10 2TN, UK

27 Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield Medical School, Western Bank, Sheffield, S10 2TN, UK

28 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield Medical School, Western Bank, Sheffield, S10 2TN, UK

29 Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK

30 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbach Str. 112, Stuttgart, 70367, Germany and University Tübingen, Wachterstrasse, Tübingen, 72074, Germany

31 Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Johanniterstraße 3, Bonn, 53113, Germany

32 Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bürkle-de-la-Camp Platz 1, Bochum, 44789, Germany

33 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

34 Institute of Pathology, Medical Faculty University of Bonn, Reuterstr. 2b, Bonn, 53113, Germany

35 Vesalius Research Center (VRC), VIB and KULeuven, Herestraat 49 B, Leuven, 3000 Belgium

36 Multidisciplinary Breast Center, University Hospital Gasthuisberg, Herestraat 49 B, Leuven, 3000, Belgium

37 Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 43. Ulm, 89075, Germany

38 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12A, Stockholm, SE-171 77, Sweden

39 Human Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome, #02-01, Singapore, 138672, Singapore

40 Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, St Andrews Pl, Melbourne, 3002, Australia

41 Australian Ovarian Cancer Study Group, Peter MacCallum Cancer Center, St Andrews Pl, Melbourne, 3002, Australia

42 Cancer Epidemiology Centre, Cancer Council Victoria, 1 Rathdowne St, Melbourne, 3053, Australia

43 Department of Epidemiology and Preventive Medicine, Monash University, Level 6 The Alfred Centre, 99 Commercial Road, Melbourne, 3004, Australia

44 Department of Clinical Biochemistry and Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, 2730, Denmark

45 Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538, USA

46 Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA

47 Department of Health Sciences Research, Mayo Clinic, 200 First Street S.W. Rochester, MN 55905, USA

48 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

49 Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Martinistrasse 52, Hamburg, 20246, Germany

50 Department of Gynecology and Obstetrics, University Hospital Erlangen, Universitätsstrasse 21 23, Erlangen, 91054 Germany

51 Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Schlossplatz 4, Erlangen, 91054, Germany

52 Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK

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Breast Cancer Research 2010, 12:R110  doi:10.1186/bcr2797

Published: 31 December 2010



Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.


We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.


These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.


The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.