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

Walker, Logan C.; Fredericksen, Zachary S.; Wang, Xianshu; Tarrell, Robert; Pankratz, Vernon S.; Lindor, Noralane M.; Beesley, Jonathan; Healey, Sue; Chen, Xiaoqing and Fab, K. Con, et al. (2010) In Breast Cancer Research 12(6).
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... (More)
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 (r(2) = 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. (Less)
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Breast Cancer Research
volume
12
issue
6
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BioMed Central
external identifiers
  • wos:000288751500013
  • scopus:78649372135
ISSN
1465-5411
DOI
10.1186/bcr2785
language
English
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yes
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26ee0cb3-8246-43bc-9ae0-fbe3e9e2c5b2 (old id 1917559)
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2011-05-03 08:24:32
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2018-05-29 12:21:02
@article{26ee0cb3-8246-43bc-9ae0-fbe3e9e2c5b2,
  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 &lt; 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r(2) = 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.},
  author       = {Walker, Logan C. and Fredericksen, Zachary S. and Wang, Xianshu and Tarrell, Robert and Pankratz, Vernon S. and Lindor, Noralane M. and Beesley, Jonathan and Healey, Sue and Chen, Xiaoqing and Fab, K. Con and Stoppa-Lyonnet, Dominique and Tirapo, Carole and Giraud, Sophie and Mazoyer, Sylvie and Muller, Daniele and Fricker, Jean-Pierre and Delnatte, Capucine and Schmutzler, Rita K. and Wappenschmidt, Barbara and Engel, Christoph and Schoenbuchner, Ines and Deissler, Helmut and Meindl, Alfons and Hogervorst, Frans B. and Verheus, Martijn and Hooning, Maartje J. and van den Ouweland, Ans M. W. and Nelen, Marcel R. and Ausems, Margreet G. E. M. and Aalfs, Cora M. and van Asperen, Christi J. and Devilee, Peter and Gerrits, Monique M. and Waisfisz, Quinten and Szabo, Csilla I. and Quad, Mod S. and Easton, Douglas F. and Peock, Susan and Cook, Margaret and Oliver, Clare T. and Frost, Debra and Harrington, Patricia and Evans, D. Gareth and Lalloo, Fiona and Eeles, Ros and Izatt, Louise and Chu, Carol and Davidson, Rosemarie and Eccles, Diana and Ong, Kai-Ren and Cook, Jackie and Rebbeck, Tim and Nathanson, Katherine L. and Domchek, Susan M. and Singer, Christian F. and Gschwantler-Kaulich, Daphne and Dressler, Anne-Catharina and Pfeiler, Georg and Godwin, Andrew K. and Heikkinen, Tuomas and Nevanlinna, Heli and Agnarsson, Bjarni A. and Caligo, Maria Adelaide and Olsson, Håkan and Kristoffersson, Ulf and Liljegren, Annelie and Arver, Brita and Karlsson, Per and Melin, Beatrice and Sinilnikova, Olga M. and McGuffog, Lesley and Antoniou, Antonis C. and Chenevix-Trench, Georgia and Spurdle, Amanda B. and Couch, Fergus J.},
  issn         = {1465-5411},
  language     = {eng},
  number       = {6},
  publisher    = {BioMed Central},
  series       = {Breast Cancer Research},
  title        = {Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1186/bcr2785},
  volume       = {12},
  year         = {2010},
}