Open Access Highly Accessed Research article

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers

Logan C Walker1, Zachary S Fredericksen2, Xianshu Wang2, Robert Tarrell2, Vernon S Pankratz2, Noralane M Lindor2, Jonathan Beesley1, Sue Healey1, Xiaoqing Chen1, kConFab3, Dominique Stoppa-Lyonnet4, Carole Tirapo4, Sophie Giraud5, Sylvie Mazoyer6, Danièle Muller7, Jean-Pierre Fricker7, Capucine Delnatte8, GEMO Study Collaborators9, Rita K Schmutzler10, Barbara Wappenschmidt10, Christoph Engel11, Ines Schönbuchner12, Helmut Deissler13, Alfons Meindl14, Frans B Hogervorst15, Martijn Verheus16, Maartje J Hooning17, Ans MW van den Ouweland18, Marcel R Nelen19, Margreet GEM Ausems20, Cora M Aalfs21, Christi J van Asperen22, Peter Devilee23, Monique M Gerrits24, Quinten Waisfisz25, HEBON15, Csilla I Szabo2, ModSQuaD2, Douglas F Easton26, Susan Peock26, Margaret Cook26, Clare T Oliver26, Debra Frost26, Patricia Harrington27, D Gareth Evans28, Fiona Lalloo28, Ros Eeles29, Louise Izatt30, Carol Chu31, Rosemarie Davidson32, Diana Eccles33, Kai-Ren Ong34, Jackie Cook35, EMBRACE26, Tim Rebbeck36, Katherine L Nathanson36, Susan M Domchek36, Christian F Singer37, Daphne Gschwantler-Kaulich37, Anne-Catharina Dressler37, Georg Pfeiler37, Andrew K Godwin38, Tuomas Heikkinen39, Heli Nevanlinna39, Bjarni A Agnarsson40, Maria Adelaide Caligo41, Håkan Olsson42, Ulf Kristoffersson43, Annelie Liljegren44, Brita Arver44, Per Karlsson45, Beatrice Melin46, SWE-BRCA47, Olga M Sinilnikova67, Lesley McGuffog26, Antonis C Antoniou26, Georgia Chenevix-Trench1, Amanda B Spurdle1* and Fergus J Couch2

Author Affiliations

1 Division of Genetics and Population Health, Queensland Institute of Medical Research, 300 Herston Road, Brisbane 4029, Australia

2 Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

3 Research Division, Peter MacCallum Cancer Center, A'Beckett Street, Melbourne, VIC 8006, Australia

4 INSERM U509, Service de Génétique Oncologique, Institut Curie, Université Paris-Descartes, 26 rue d'Ulm, 75248 Paris cedex 05, France

5 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 Rue Laennec, 69008 Lyon, France

6 Equipe labellisée LIGUE 2008, UMR5201 CNRS, Centre Léon Bérard, Université de Lyon, 28 Rue Laennec, 69008 Lyon, France

7 Unité d'Oncogénétique, CLCC Paul Strauss, 3 rue de la Porte de l'Hoˆpital BP42, 67065 Strasbourg Cedex, France

8 Centre René Gauducheau, Boulevard Jacques Monod, Nantes 44805 Saint Herblain Cedex, France

9 Cancer Genetics Network 12 "Groupe Génétique et Cancer", Fédération Nationale des Centres de Lutte Contre le Cancer, 101 Rue de Tolbiac, 75654 Paris Cedex 13, France

10 Centre for Hereditary Breast and Ovarian Cancer, Department of Obstetrics and Gynaecology, University of Cologne, Albertus-Magnus-Platz, 50923 Cologne, Germany

11 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Ritterstraße 26, 04109 Leipzig, Germany

12 Institute of Human Genetics, University of Würzburg, Sander Ring 2, 97070 Würzburg, Germany

13 Department of Obstetrics and Gynaecology, University of Ulm, Oberer Eselsberg 11, 89069 Ulm, Germany

14 Department of Obstetrics and Gynaecology, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Arcisstraße 21, 80333 Munich, Germany

15 Family Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands

16 Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands

17 Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands

18 Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands

19 Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands

20 Department of Medical Genetics, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands

21 Department of Clinical Genetics, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands

22 Department of Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

23 Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

24 Department of Genetics and Cell Biology, University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands

25 Department of Clinical Genetics, VU University Medical Center, De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands

26 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK

27 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK

28 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Hathersage Road, Manchester M13 9LW, UK

29 Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK

30 Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, Guys Hospital, St Thomas Street, London SE1 9RT, UK

31 Yorkshire Regional Genetics Service, St. James's Hospital, Beckett Street, Leeds LS9 TF7, UK

32 Ferguson-Smith Centre for Clinical Genetics, Block 4 Yorhill NHS Trust, Yorkhill, Glasgow G3 8SJ, UK

33 Wessex Clinical Genetics Service and Cancer Sciences Division, Princess Anne Hospital, Southampton SO16 5YA, UK

34 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG, UK

35 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield, S10 2JF, UK

36 Abramson Cancer Center, University of Pennsylvania School of Medicine, 531 BRB 2/3, 421 Curie Boulevard, Philadelphia, PA 19104, USA

37 Division of Special Gynecology, Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria

38 Women's Cancer Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

39 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland

40 Department of Pathology, University Hospital and University of Iceland School of Medicine, 101 Reykjavik, Iceland

41 Section of Genetic Oncology, University Hospital of Pisa, Via Roma 57, Pisa 56127, Italy

42 Department of Oncology, Lund University Hospital, S-22185 Lund, Sweden

43 Department of Clinical Genetics, Lund University Hospital, S-22185 Lund, Sweden

44 Department of Oncology, Karolinska University Hospital, 171 64 Solna, Stockholm, Sweden

45 Department of Oncology, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden

46 Department of Radiation Sciences, Oncology, Umeå University, SE-901 87 Umeå, Sweden

47 Department of Oncology, Clinical Sciences Lund, Lund University, SE 221 85 Lund, Sweden

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Breast Cancer Research 2010, 12:R102  doi:10.1186/bcr2785

Published: 29 November 2010

Abstract

Introduction

Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.

Methods

We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

Results

SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, Ptrend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, Ptrend = 0.018).

Conclusions

This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.