Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010;12(6):R102.
doi: 10.1186/bcr2785. Epub 2010 Nov 29.

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

Logan C Walker  1 , 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
Affiliations

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

Logan C Walker et al. Breast Cancer Res. 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, 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
BRCA2 plot of relative risk for rs3825977 and rs7166081 at the SMAD3 locus. BRCA2 plots of study group-specific relative risk (RR) for rs3825977 and rs7166081 at the SMAD3 locus. Study groups with 70 or more carriers and tests of heterogeneity are shown for (a) rs3825977 (overall RR (95% confidence interval (CI)) = 1.20 (1.03, 1.40), Ptrend = 0.018) and (b) rs7166081 (overall RR (95% CI) = 1.25 (1.07, 1.45), Ptrend = 0.004). OR, odds ratio.
See this image and copyright information in PMC

References

    1. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjakoski K, Kallioniemi OP, Thompson D, Evans C, Peto J. et al.Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117–1130. doi: 10.1086/375033. - DOI - PMC - PubMed
    1. Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, Peterson LE, Schildkraut JM, Isaacs C, Peshkin BN, Corio C, Leondaridis L, Tomlinson G, Dutson D, Kerber R, Amos CI, Strong LC, Berry DA, Euhus DM, Parmigiani G. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006;24:863–871. doi: 10.1200/JCO.2005.03.6772. - DOI - PMC - PubMed
    1. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995;56:265–271. - PMC - PubMed
    1. Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995;57:1457–1462. - PMC - PubMed
    1. Milne RL, Osorio A, Cajal TR, Vega A, Llort G, de la Hoya M, Diez O, Alonso MC, Lazaro C, Blanco I, Sanchez-de-Abajo A, Caldes T, Blanco A, Grana B, Duran M, Velasco E, Chirivella I, Cardenosa EE, Tejada MI, Beristain E, Miramar MD, Calvo MT, Martinez E, Guillen C, Salazar R, San Roman C, Antoniou AC, Urioste M, Benitez J. The average cumulative risks of breast and ovarian cancer for carriers of mutations in BRCA1 and BRCA2 attending genetic counseling units in Spain. Clin Cancer Res. 2008;14:2861–2869. doi: 10.1158/1078-0432.CCR-07-4436. - DOI - PubMed

Substances