Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 6/2010

Open Access 01-12-2010 | Research article

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2mutation carriers

Authors: Logan C Walker, Zachary S Fredericksen, Xianshu Wang, Robert Tarrell, Vernon S Pankratz, Noralane M Lindor, Jonathan Beesley, Sue Healey, Xiaoqing Chen, Dominique Stoppa-Lyonnet, Carole Tirapo, Sophie Giraud, Sylvie Mazoyer, Danièle Muller, Jean-Pierre Fricker, Capucine Delnatte, 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, Csilla I Szabo, 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, 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, Olga M Sinilnikova, Lesley McGuffog, Antonis C Antoniou, Georgia Chenevix-Trench, Amanda B Spurdle, Fergus J Couch, kConFab, GEMO Study Collaborators, HEBON, ModSQuaD, EMBRACE, SWE-BRCA

Published in: Breast Cancer Research | Issue 6/2010

Login to get access

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.
Appendix
Available only for authorised users
Literature
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. 10.1086/375033.CrossRefPubMedPubMedCentral
2.
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. 10.1200/JCO.2005.03.6772.CrossRefPubMedPubMedCentral
3.
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.CrossRefPubMedPubMedCentral
4.
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.PubMedPubMedCentral
5.
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. 10.1158/1078-0432.CCR-07-4436.CrossRefPubMed
6.
Simchoni S, Friedman E, Kaufman B, Gershoni-Baruch R, Orr-Urtreger A, Kedar-Barnes I, Shiri-Sverdlov R, Dagan E, Tsabari S, Shohat M, Catane R, King MC, Lahad A, Levy-Lahad E: Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci USA. 2006, 103: 3770-3774. 10.1073/pnas.0511301103.CrossRefPubMedPubMedCentral
7.
Antoniou AC, Sinilnikova OM, Simard J, Leone M, Dumont M, Neuhausen SL, Struewing JP, Stoppa-Lyonnet D, Barjhoux L, Hughes DJ, Coupier I, Belotti M, Lasset C, Bonadona V, Bignon YJ, Rebbeck TR, Wagner T, Lynch HT, Domchek SM, Nathanson KL, Garber JE, Weitzel J, Narod SA, Tomlinson G, Olopade OI, Godwin A, Isaacs C, Jakubowska A, Lubinski J, Gronwald J, et al: RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet. 2007, 81: 1186-1200. 10.1086/522611.CrossRefPubMedPubMedCentral
8.
Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kampjarvi K, Nevanlinna H, Simard J, Beesley J, Chen X, Neuhausen SL, Rebbeck TR, Wagner T, Lynch HT, Isaacs C, Weitzel J, Ganz PA, Daly MB, Tomlinson G, Olopade OI, et al: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008, 82: 937-948. 10.1016/j.ajhg.2008.02.008.CrossRefPubMedPubMedCentral
9.
Couch FJ, Sinilnikova O, Vierkant RA, Pankratz VS, Fredericksen ZS, Stoppa-Lyonnet D, Coupier I, Hughes D, Hardouin A, Berthet P, Peock S, Cook M, Baynes C, Hodgson S, Morrison PJ, Porteous ME, Jakubowska A, Lubinski J, Gronwald J, Spurdle AB, Schmutzler R, Versmold B, Engel C, Meindl A, Sutter C, Horst J, Schaefer D, Offit K, Kirchhoff T, Andrulis IL, et al: AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. Cancer Epidemiol Biomarkers Prev. 2007, 16: 1416-1421. 10.1158/1055-9965.EPI-06-0783.CrossRefPubMedPubMedCentral
10.
Johnatty SE, Couch FJ, Fredericksen Z, Tarrell R, Spurdle AB, Beesley J, Chen X, Gschwantler-Kaulich D, Singer CF, Fuerhauser C, Fink-Retter A, Domchek SM, Nathanson KL, Pankratz VS, Lindor NM, Godwin AK, Caligo MA, Hopper J, Southey MC, Giles GG, Justenhoven C, Brauch H, Hamann U, Ko YD, Heikkinen T, Aaltonen K, Aittomaki K, Blomqvist C, Nevanlinna H, Hall P, et al: No evidence that GATA3 rs570613 SNP modifies breast cancer risk. Breast Cancer Res Treat. 2009, 117: 371-379. 10.1007/s10549-008-0257-1.CrossRefPubMed
11.
Rebbeck TR, Antoniou AC, Llopis TC, Nevanlinna H, Aittomaki K, Simard J, Spurdle AB, Couch FJ, Pereira LH, Greene MH, Andrulis IL, Pasche B, Kaklamani V, Hamann U, Szabo C, Peock S, Cook M, Harrington PA, Donaldson A, Male AM, Gardiner CA, Gregory H, Side LE, Robinson AC, Emmerson L, Ellis I, Peyrat JP, Fournier J, Vennin P, Adenis C, et al: No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study. Breast Cancer Res Treat. 2009, 115: 185-192. 10.1007/s10549-008-0064-8.CrossRefPubMed
12.
Antoniou AC, Sinilnikova OM, McGuffog L, Healey S, Nevanlinna H, Heikkinen T, Simard J, Spurdle AB, Beesley J, Chen X, Neuhausen SL, Ding YC, Couch FJ, Wang X, Fredericksen Z, Peterlongo P, Peissel B, Bonanni B, Viel A, Bernard L, Radice P, Szabo CI, Foretova L, Zikan M, Claes K, Greene MH, Mai PL, Rennert G, Lejbkowicz F, Andrulis IL, et al: Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 2009, 18: 4442-4456. 10.1093/hmg/ddp372.CrossRefPubMedPubMedCentral
13.
Jakubowska A, Rozkrut D, Antoniou A, Hamann U, Lubinski J: The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat. 2010, 121: 639-649. 10.1007/s10549-009-0595-7.CrossRefPubMed
14.
Osorio A, Milne RL, Pita G, Peterlongo P, Heikkinen T, Simard J, Chenevix-Trench G, Spurdle AB, Beesley J, Chen X, Healey S, Neuhausen SL, Ding YC, Couch FJ, Wang X, Lindor N, Manoukian S, Barile M, Viel A, Tizzoni L, Szabo CI, Foretova L, Zikan M, Claes K, Greene MH, Mai P, Rennert G, Lejbkowicz F, Barnett-Griness O, Andrulis IL, et al: Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA). Br J Cancer. 2009, 101: 2048-2054. 10.1038/sj.bjc.6605416.CrossRefPubMedPubMedCentral
15.
Sinilnikova OM, Antoniou AC, Simard J, Healey S, Leone M, Sinnett D, Spurdle AB, Beesley J, Chen X, Greene MH, Loud JT, Lejbkowicz F, Rennert G, Dishon S, Andrulis IL, Domchek SM, Nathanson KL, Manoukian S, Radice P, Konstantopoulou I, Blanco I, Laborde AL, Duran M, Osorio A, Benitez J, Hamann U, Hogervorst FB, van Os TA, Gille HJ, Peock S, et al: The TP53 Arg72Pro and MDM2 309G > T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2009, 101: 1456-1460. 10.1038/sj.bjc.6605279.CrossRefPubMedPubMedCentral
16.
Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le Marchand L, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, et al: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007, 447: 1087-1093. 10.1038/nature05887.CrossRefPubMedPubMedCentral
17.
Chenevix-Trench G, Milne RL, Antoniou AC, Couch FJ, Easton DF, Goldgar DE: An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res. 2007, 9: 104-10.1186/bcr1670.CrossRefPubMedPubMedCentral
18.
Walker LC, Waddell N, Ten Haaf A, Grimmond S, Spurdle AB: Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers. Breast Cancer Res Treat. 2008, 112: 229-236. 10.1007/s10549-007-9848-5.CrossRefPubMed
19.
20.
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF, Hoover RN, Thomas G, Chanock SJ: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007, 39: 870-874. 10.1038/ng2075.CrossRefPubMedPubMedCentral
21.
Azzato EM, Tyrer J, Fasching PA, Beckmann MW, Ekici AB, Schulz-Wendtland R, Bojesen SE, Nordestgaard BG, Flyger H, Milne RL, Arias JI, Menendez P, Benitez J, Chang-Claude J, Hein R, Wang-Gohrke S, Nevanlinna H, Heikkinen T, Aittomaki K, Blomqvist C, Margolin S, Mannermaa A, Kosma VM, Kataja V, Beesley J, Chen X, Chenevix-Trench G, Couch FJ, Olson JE, Fredericksen ZS, et al: Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival. J Natl Cancer Inst. 2010, 102: 650-662. 10.1093/jnci/djq057.CrossRefPubMedPubMedCentral
22.
Steemers FJ, Gunderson KL: Illumina, Inc. Pharmacogenomics. 2005, 6: 777-782. 10.2217/14622416.6.7.777.CrossRefPubMed
23.
Antoniou AC, Goldgar DE, Andrieu N, Chang-Claude J, Brohet R, Rookus MA, Easton DF: A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol. 2005, 29: 1-11. 10.1002/gepi.20074.CrossRefPubMed
24.
Kramer JL, Velazquez IA, Chen BE, Rosenberg PS, Struewing JP, Greene MH: Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol. 2005, 23: 8629-8635. 10.1200/JCO.2005.02.9199.CrossRefPubMed
25.
Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, Evans G, Isaacs C, Daly MB, Matloff E, Olopade OI, Weber BL: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002, 346: 1616-1622. 10.1056/NEJMoa012158.CrossRefPubMed
26.
27.
Preobrazhenska O, Yakymovych M, Kanamoto T, Yakymovych I, Stoika R, Heldin CH, Souchelnytskyi S: BRCA2 and Smad3 synergize in regulation of gene transcription. Oncogene. 2002, 21: 5660-5664. 10.1038/sj.onc.1205732.CrossRefPubMed
28.
29.
Yang WT, Lewis MT, Hess K, Wong H, Tsimelzon A, Karadag N, Cairo M, Wei C, Meric-Bernstam F, Brown P, Arun B, Hortobagyi GN, Sahin A, Chang JC: Decreased TGFβ signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res Treat. 2010, 119: 305-314. 10.1007/s10549-009-0350-0.CrossRefPubMed
30.
Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, Sinilnikova OM, Healey S, Morrison J, Kartsonaki C, Lesnick T, Ghoussaini M, Barrowdale D, Peock S, Cook M, Oliver C, Frost D, Eccles D, Evans DG, Eeles R, Izatt L, Chu C, Douglas F, Paterson J, Stoppa-Lyonnet D, Houdayer C, Mazoyer S, Giraud S, Lasset C, Remenieras A, Caron O, et al: A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet. 2010, 42: 885-892. 10.1038/ng.669.CrossRefPubMedPubMedCentral
Metadata
Title
Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2mutation carriers
Authors
Logan C Walker
Zachary S Fredericksen
Xianshu Wang
Robert Tarrell
Vernon S Pankratz
Noralane M Lindor
Jonathan Beesley
Sue Healey
Xiaoqing Chen
Dominique Stoppa-Lyonnet
Carole Tirapo
Sophie Giraud
Sylvie Mazoyer
Danièle Muller
Jean-Pierre Fricker
Capucine Delnatte
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
Csilla I Szabo
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
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
Olga M Sinilnikova
Lesley McGuffog
Antonis C Antoniou
Georgia Chenevix-Trench
Amanda B Spurdle
Fergus J Couch
kConFab
GEMO Study Collaborators
HEBON
ModSQuaD
EMBRACE
SWE-BRCA
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2010
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2785

Other articles of this Issue 6/2010

Breast Cancer Research 6/2010 Go to the issue

Research article

Cystatin M loss is associated with the losses of estrogen receptor, progesterone receptor, and HER4 in invasive breast cancer

Review

Key signaling nodes in mammary gland development and cancer: β-catenin

Editorial

Pre-analytic variables and phospho-specific antibodies: the Achilles heel of immunohistochemistry

Review

Prevention of bone metastases and management of bone health in early breast cancer

Research article

Lifetime risks of specific breast cancer subtypes among women in four racial/ethnic groups

Research article

A PALB2 mutation associated with high risk of breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits