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

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

R102
Walker, Logan C.
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Fredericksen, Zachary S.
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Wang, Xianshu
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Tarrell, Robert
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Pankratz, Vernon S.
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Healey, Sue
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Chen, Xiaoqing
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Stoppa-Lyonnet, Dominique
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Tirapo, Carole
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Giraud, Sophie
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Mazoyer, Sylvie
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Deissler, Helmut
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van den Ouweland, Ans M.W.
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Nelen, Marcel R.
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Aalfs, Cora M.
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van Asperen, Christi J.
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Devilee, Peter
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Gerrits, Monique M.
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Waisfisz, Quinten
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Szabo, Csilla I.
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Easton, Douglas F.
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Peock, Susan
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Cook, Margaret
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Oliver, Clare T.
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Frost, Debra
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Harrington, Patricia
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Evans, D. Gareth
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Lalloo, Fiona
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Eeles, Ros
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Izatt, Louise
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Chu, Carol
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Davidson, Rosemarie
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Eccles, Diana
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Ong, Kai-Ren
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Cook, Jackie
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Rebbeck, Tim
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GEMO Study Collaborators
Walker, Logan C.
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Fredericksen, Zachary S.
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Wang, Xianshu
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Tarrell, Robert
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Pankratz, Vernon S.
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Lindor, Noralane M.
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Beesley, Jonathan
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Healey, Sue
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Chen, Xiaoqing
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Stoppa-Lyonnet, Dominique
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Tirapo, Carole
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Giraud, Sophie
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Mazoyer, Sylvie
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Muller, Daniele
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Fricker, Jean-Pierre
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Delnatte, Capucine
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Schmutzler, Rita K.
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Wappenschmidt, Barbara
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Engel, Christoph
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Schonbuchner, Ines
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Deissler, Helmut
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Meindl, Alfons
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Hogervorst, Frans B.
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Verheus, Martijn
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Hooning, Maartje J.
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van den Ouweland, Ans M.W.
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Nelen, Marcel R.
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Devilee, Peter
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Gerrits, Monique M.
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Easton, Douglas F.
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Peock, Susan
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Cook, Margaret
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Oliver, Clare T.
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Frost, Debra
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Harrington, Patricia
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Lalloo, Fiona
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Eeles, Ros
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Izatt, Louise
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Chu, Carol
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Davidson, Rosemarie
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Eccles, Diana
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Ong, Kai-Ren
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Cook, Jackie
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Rebbeck, Tim
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Walker, Logan C., Fredericksen, Zachary S., Wang, Xianshu, Tarrell, Robert, Pankratz, Vernon S., Lindor, Noralane M., Beesley, Jonathan, Healey, Sue, Chen, Xiaoqing, Stoppa-Lyonnet, Dominique, Tirapo, Carole, Giraud, Sophie, Mazoyer, Sylvie, Muller, Daniele, Fricker, Jean-Pierre, Delnatte, Capucine, Schmutzler, Rita K., Wappenschmidt, Barbara, Engel, Christoph, Schonbuchner, Ines, Deissler, Helmut, Meindl, Alfons, Hogervorst, Frans B., Verheus, Martijn, Hooning, Maartje J., van den Ouweland, Ans M.W., Nelen, Marcel R., Ausems, Margreet G.E.M., Aalfs, Cora M., van Asperen, Christi J., Devilee, Peter, Gerrits, Monique M., Waisfisz, Quinten, Szabo, Csilla I., 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 and Rebbeck, Tim , GEMO Study Collaborators (2010) Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Research, 12 (6), R102. (doi:10.1186/bcr2785). (PMID:21114847)

Record type: Article

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.

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More information

Published date: 29 November 2010

Identifiers

Local EPrints ID: 180175
URI: http://eprints.soton.ac.uk/id/eprint/180175
PURE UUID: 4afa63dc-4387-49ed-ad9a-a2d6cc7008e0
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 05 Apr 2011 14:54
Last modified: 15 Mar 2024 02:40

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Contributors

Author: Logan C. Walker
Author: Zachary S. Fredericksen
Author: Xianshu Wang
Author: Robert Tarrell
Author: Vernon S. Pankratz
Author: Noralane M. Lindor
Author: Jonathan Beesley
Author: Sue Healey
Author: Xiaoqing Chen
Author: Dominique Stoppa-Lyonnet
Author: Carole Tirapo
Author: Sophie Giraud
Author: Sylvie Mazoyer
Author: Daniele Muller
Author: Jean-Pierre Fricker
Author: Capucine Delnatte
Author: Rita K. Schmutzler
Author: Barbara Wappenschmidt
Author: Christoph Engel
Author: Ines Schonbuchner
Author: Helmut Deissler
Author: Alfons Meindl
Author: Frans B. Hogervorst
Author: Martijn Verheus
Author: Maartje J. Hooning
Author: Ans M.W. van den Ouweland
Author: Marcel R. Nelen
Author: Margreet G.E.M. Ausems
Author: Cora M. Aalfs
Author: Christi J. van Asperen
Author: Peter Devilee
Author: Monique M. Gerrits
Author: Quinten Waisfisz
Author: Csilla I. Szabo
Author: Douglas F. Easton
Author: Susan Peock
Author: Margaret Cook
Author: Clare T. Oliver
Author: Debra Frost
Author: Patricia Harrington
Author: D. Gareth Evans
Author: Fiona Lalloo
Author: Ros Eeles
Author: Louise Izatt
Author: Carol Chu
Author: Rosemarie Davidson
Author: Diana Eccles ORCID iD
Author: Kai-Ren Ong
Author: Jackie Cook
Author: Tim Rebbeck
Corporate Author: GEMO Study Collaborators

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