Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2mutation carriers
Authors: Walker Logan C , Fredericksen Zachary S , Wang Xianshu , Tarrell Robert , Pankratz Vernon S , Lindor Noralane M , Beesley Jonathan , Healey Sue , Chen Xiaoqing ,   kConFab, Stoppa-Lyonnet Dominique , Tirapo Carole , Giraud Sophie , Mazoyer Sylvie , Muller Danièle , Fricker Jean-Pierre , Delnatte Capucine ,   GEMO Study Collaborators, Schmutzler Rita K , Wappenschmidt Barbara , Engel Christoph , Schönbuchner Ines , Deissler Helmut , Meindl Alfons , Hogervorst Frans B , Verheus Martijn , Hooning Maartje J , van den Ouweland Ans MW , Nelen Marcel R , Ausems Margreet GEM , Aalfs Cora M , van Asperen Christi J , Devilee Peter , Gerrits Monique M , Waisfisz Quinten ,   HEBON, Szabo Csilla I ,   ModSQuaD, Easton Douglas F , Peock Susan , Cook Margaret , Oliver Clare T , Frost Debra , Harrington Patricia , Evans D Gareth , Lalloo Fiona , Eeles Ros , Izatt Louise , Chu Carol , Davidson Rosemarie , Eccles Diana , Ong Kai-Ren , Cook Jackie ,   EMBRACE, Rebbeck Tim , Nathanson Katherine L , Domchek Susan M , Singer Christian F , Gschwantler-Kaulich Daphne , Dressler Anne-Catharina , Pfeiler Georg , Godwin Andrew K , Heikkinen Tuomas , Nevanlinna Heli , Agnarsson Bjarni A , Caligo Maria Adelaide , Olsson Håkan , Kristoffersson Ulf , Liljegren Annelie , Arver Brita , Karlsson Per , Melin Beatrice ,   SWE-BRCA, Sinilnikova Olga M , McGuffog Lesley , Antoniou Antonis C , Chenevix-Trench Georgia , Spurdle Amanda B , Couch Fergus J 
Published: 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.