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

Logan Walker 1 Zachary Fredericksen 2 Xianshu Wang 2 Robert Tarrell 2 Vernon Pankratz 2 Noralane Lindor 2 Jonathan Beesley 1 Sue Healey 1 Xiaoqing Chen 1 Dominique Stoppa-Lyonnet 3 Carole Tirapo 3 Sophie Giraud 4 Sylvie Mazoyer 5 Danièle Muller 6 Jean-Pierre Fricker 6 Capucine Delnatte 7 Rita Schmutzler 8 Barbara Wappenschmidt 8 Christoph Engel 9 Ines Schönbuchner 10 Helmut Deissler 11 Alfons Meindl 12 Frans Hogervorst 13 Martijn Verheus 14 Maartje Hooning 15 Ans van den Ouweland 16 Marcel Nelen 17 Margreet Ausems 18 Cora Aalfs 19 Christi van Asperen 20 Peter Devilee 21 Monique Gerrits 22 Quinten Waisfisz 23 Csilla Szabo 2 Douglas Easton 24 Susan Peock 24 Margaret Cook 24 Clare Oliver 24 Debra Frost 24 Patricia Harrington 25 Gareth D. Evans 26 Fiona Lalloo 26 Ros Eeles 27 Louise Izatt 28 Carol Chu 29 Rosemarie Davidson 30 Diana Eccles 31 Kai-Ren Ong 32 Jackie Cook 33 Tim Rebbeck 34 Katherine Nathanson 34 Susan Domchek 34 Christian Singer 35 Daphne Gschwantler-Kaulich 35 Anne-Catharina Dressler 35 Georg Pfeiler 35 Andrew Godwin 36 Tuomas Heikkinen 37 Heli Nevanlinna 37 Bjarni Agnarsson 38 Maria Adelaide Caligo 39 Håkan Olsson 40 Ulf Kristoffersson 41 Annelie Liljegren 42 Brita Arver 42 Per Karlsson 43 Beatrice Melin 44 Olga Sinilnikova 5, 6 Lesley Mcguffog 24 Antonis Antoniou 24 Georgia Chenevix-Trench 1 Amanda Spurdle 1, * Fergus Couch 2 
* Corresponding author
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.
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Logan Walker, Zachary Fredericksen, Xianshu Wang, Robert Tarrell, Vernon Pankratz, et al.. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.. Breast Cancer Research, BioMed Central, 2010, 12 (6), pp.R102. ⟨10.1186/bcr2785⟩. ⟨inserm-00622882⟩



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