Year: 2010
Type: article
Study design: Observational Study
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, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 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.
Source: Breast Cancer Research
DOI: 10.1186/bcr2785
Authors: Logan C Walker, Zachary S Fredericksen, Xianshu Wang, Robert Tarrell, Vernon S Pankratz, Noralane M Lindor, Jonathan Beesley, Sue Healey, Xiaoqing Chen, kConFab, Dominique Stoppa-Lyonnet, Carole Tirapo, Sophie Giraud, Sylvie Mazoyer, Danièle Muller, Jean-Pierre Fricker, Capucine Delnatte, GEMO Study Collaborators, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Ines Schönbuchner, Helmut Deissler, Alfons Meindl, Frans B Hogervorst, Martijn Verheus, Maartje J Hooning, Ans MW van den Ouweland, Marcel R Nelen, Margreet GEM Ausems, Cora M Aalfs, Christi J van Asperen, Peter Devilee, Monique M Gerrits, Quinten Waisfisz, HEBON, Csilla I Szabo, ModSQuaD, Douglas F Easton, Susan Peock, Margaret Cook, Clare T Oliver, Debra Frost, Patricia Harrington, D Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Carol Chu, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, EMBRACE, Tim Rebbeck, Katherine L Nathanson, Susan M Domchek, Christian F Singer, Daphne Gschwantler-Kaulich, Anne-Catharina Dressler, Georg Pfeiler, Andrew K Godwin, Tuomas Heikkinen, Heli Nevanlinna, Bjarni A Agnarsson, Maria Adelaide Caligo, Håkan Olsson, Ulf Kristoffersson, Annelie Liljegren, Brita Arver, Per Karlsson, Beatrice Melin, SWE-BRCA, Olga M Sinilnikova, Lesley McGuffog, Antonis C Antoniou, Georgia Chenevix-Trench, Amanda B Spurdle, Fergus J Couch
Institutions: QIMR Berghofer Medical Research Institute, Mayo Clinic, Inserm, Université Paris Descartes, Institut Curie, Hospices Civils de Lyon, Centre Léon Bérard, Centre National de la Recherche Scientifique, Université de Lyon, Institut Strauss, University of Cologne, Leipzig University, University of Würzburg, Universität Ulm, TUM Klinikum, Technical University of Munich, The Netherlands Cancer Institute, Erasmus MC, Radboud University Medical Center, University Medical Center Utrecht, Amsterdam UMC Location University of Amsterdam, Leiden University Medical Center, Maastricht University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, University of Cambridge, Manchester Academic Health Science Centre, St Mary's Hospital, Royal Marsden NHS Foundation Trust, Institute of Cancer Research, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, Princess Anne Hospital, Birmingham Women's Hospital, Sheffield Children's Hospital, Abramson Cancer Center, University of Pennsylvania, Medical University of Vienna, Fox Chase Cancer Center, Helsinki University Hospital, University of Iceland, Azienda Ospedaliera Universitaria Pisana, Lund University, Karolinska University Hospital, Sahlgrenska University Hospital, Umeå University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Funders: Breast Cancer Research Foundation, University of Pennsylvania, Univerzita Karlova v Praze, Georgetown University, Helsingin ja Uudenmaan Sairaanhoitopiiri, Royal Marsden NHS Foundation Trust, Cancer Research UK, National Institute for Health and Care Research, Universiteit Leiden, Radboud Universiteit, Vrije Universiteit Amsterdam, Erasmus Medisch Centrum, Universität Wien, Fonds Wetenschappelijk Onderzoek, Lunds Universitet, Linköpings Universitet, Istituto Toscano Tumori, Universiteit Gent, KWF Kankerbestrijding, Umeå Universitet, Leids Universitair Medisch Centrum, Universitair Medisch Centrum Groningen, Akademiska Sjukhuset, Sahlgrenska Universitetssjukhuset, Medizinische Universität Wien, Radboud Universitair Medisch Centrum, Uppsala Universitet, Vlaamse regering, Fox Chase Cancer Center, lékařská fakulta Univerzity Karlovy, National Health and Medical Research Council, National Cancer Institute
Awards: How can the risk of breast cancer be reduced in those with a strong family history of the disease?, A genome-wide association study for breast cancer in BRCA1 mutation carriers, G1232765841, G1339790776, G236237718, G2443079445, G2514509764, Clinical Outcomes In Individuals With An Inherited Predisposition To Breast Cancer, G3891343362, G4197410787, G424082930, G4333708648, G4662672464, G5525622839, G5865683244, G6148127843, G6279653796, G6642005126, G7242219286, G7456659913, G769513066
OpenAlex ID: W2160191032