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

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 D. Delnatte; Rita K. Schmutzler; Barbara Wappenschmidt; Christoph Engel; Ines Schönbuchner; Helmut Deissler; Alfons Meindl; Frans B. Hogervorst; Martijn Verheus; Maartje J. Hooning; Ans M.W. van den Ouweland; Marcel R. Nelen; Margreet G.E.M. 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 A. 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

doi:10.1186/bcr2785

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

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 D. Delnatte, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Ines SchönbuchnerHelmut Deissler, Alfons Meindl, Frans B. Hogervorst, Martijn Verheus, Maartje J. Hooning, Ans M.W. van den Ouweland, Marcel R. Nelen, Margreet G.E.M. 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 A. 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

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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.

Original language	English (US)
Article number	R102
Journal	Breast Cancer Research
Volume	12
Issue number	6
DOIs	https://doi.org/10.1186/bcr2785
State	Published - Nov 29 2010

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1186/bcr2785

Cite this

Walker, L. C., Fredericksen, Z. S., Wang, X., Tarrell, R., Pankratz, V. S., Lindor, N. M., Beesley, J., Healey, S., Chen, X., Stoppa-Lyonnet, D., Tirapo, C., Giraud, S., Mazoyer, S., Muller, D., Fricker, J. P., Delnatte, C. D., Schmutzler, R. K., Wappenschmidt, B., Engel, C., ... Couch, F. J. (2010). Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Research, 12(6), Article R102. https://doi.org/10.1186/bcr2785

Walker, LC, Fredericksen, ZS, Wang, X, Tarrell, R, Pankratz, VS, Lindor, NM, Beesley, J, Healey, S, Chen, X, Stoppa-Lyonnet, D, Tirapo, C, Giraud, S, Mazoyer, S, Muller, D, Fricker, JP, Delnatte, CD, Schmutzler, RK, Wappenschmidt, B, Engel, C, Schönbuchner, I, Deissler, H, Meindl, A, Hogervorst, FB, Verheus, M, Hooning, MJ, van den Ouweland, AMW, Nelen, MR, Ausems, MGEM, Aalfs, CM, van Asperen, CJ, Devilee, P, Gerrits, MM, Waisfisz, Q, Szabo, CI, Easton, DF, Peock, S, Cook, M, Oliver, CT, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Eccles, D, Ong, KR, Cook, J, Rebbeck, T, Nathanson, KL, Domchek, SM, Singer, CF, Gschwantler-Kaulich, D, Dressler, AC, Pfeiler, G, Godwin, AK, Heikkinen, T, Nevanlinna, H, Agnarsson, BA, Caligo, MA, Olsson, H, Kristoffersson, U, Liljegren, A, Arver, B, Karlsson, P, Melin, B, Sinilnikova, OM, McGuffog, L, Antoniou, AC, Chenevix-Trench, G, Spurdle, AB & Couch, FJ 2010, 'Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers', Breast Cancer Research, vol. 12, no. 6, R102. https://doi.org/10.1186/bcr2785

@article{6be37e6bdfba4d09a79833a2e17315b2,

title = "Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers",

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.",

author = "Walker, {Logan C.} and Fredericksen, {Zachary S.} and Xianshu Wang and Robert Tarrell and Pankratz, {Vernon S.} and Lindor, {Noralane M.} and Jonathan Beesley and Sue Healey and Xiaoqing Chen and Dominique Stoppa-Lyonnet and Carole Tirapo and Sophie Giraud and Sylvie Mazoyer and Dani{\`e}le Muller and Fricker, {Jean Pierre} and Delnatte, {Capucine D.} and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Christoph Engel and Ines Sch{\"o}nbuchner and Helmut Deissler and Alfons Meindl and Hogervorst, {Frans B.} and Martijn Verheus 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 Peter Devilee and Gerrits, {Monique M.} and Quinten Waisfisz and Szabo, {Csilla I.} and Easton, {Douglas F.} and Susan Peock and Margaret Cook and Oliver, {Clare T.} and Debra Frost and Patricia Harrington and Evans, {D. Gareth} and Fiona Lalloo and Ros Eeles and Louise Izatt and Carol Chu and Rosemarie Davidson and Diana Eccles and Ong, {Kai Ren} and Jackie Cook and Tim Rebbeck and Nathanson, {Katherine L.} and Domchek, {Susan M.} and Singer, {Christian F.} and Daphne Gschwantler-Kaulich and Dressler, {Anne Catharina} and Georg Pfeiler and Godwin, {Andrew K.} and Tuomas Heikkinen and Heli Nevanlinna and Agnarsson, {Bjarni A.} and Caligo, {Maria A.} and H{\aa}kan Olsson and Ulf Kristoffersson and Annelie Liljegren and Brita Arver and Per Karlsson and Beatrice Melin and Sinilnikova, {Olga M.} and Lesley McGuffog and Antoniou, {Antonis C.} and Georgia Chenevix-Trench and Spurdle, {Amanda B.} and Couch, {Fergus J.}",

note = "Funding Information: GC-HBOC is supported by a grant of the German Cancer Aid (grant107054) to RKS. The authors thank Juliane K{\"o}hler for her excellent technical assistance and the centres of the GC-HBOC for providing samples and clinical data. The HEBCS study was supported by Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. The authors thank Dr Kristiina Aittom{\"a}ki, Dr Carl Blomqvist and Dr Kirsimari Aaltonen as well as RN Hanna J{\"a}ntti for their help with patient data and samples. The Pisa Breast Cancer Study (PBCS) acknowledges Fondazione Cassa di Risparmio di Pisa, Istituto Toscano Tumori. The Fox Chase Cancer Center (FCCC) acknowledges Ms JoEllen Weaver, Mr John Malick and Dr Betsy Bove for expert technical assistance. AKG was funded by SPORE P50 CA83638, U01 CA69631, 5U01 CA113916, and the Eileen Stein Jacoby Fund. The Medical University of Vienna (MUV) collaborators include CF Singer, D Gschwantler-Kaulich, G Pfeiler, and A-C Spiess. This research project has been supported by the Austrian Society for Endocrinological Oncology and by the Comprehensive Cancer Center, Cluster Genetics and Epigenetics. Georgetown acknowledges Claudine Isaacs and is supported by a National Cancer Institute Cancer Centre Support Grant to the Lombardi Comprehensive Cancer Centre (NCI P30 CA51008-12), Georgetown University, Washington, DC, USA. LCW is a John Gavin Postdoctoral Fellow (Genesis Oncology Trust), ABS is an NHMRC Senior Research Fellow, and GCT is an NHMRC Senior Principal Research Fellow. ACA is a Cancer Research UK Senior Cancer Research Fellow, and LM, the CIMBA genotyping and data management are funded by Cancer Research - UK.",

year = "2010",

month = nov,

day = "29",

doi = "10.1186/bcr2785",

language = "English (US)",

volume = "12",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central",

number = "6",

}

TY - JOUR

T1 - Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers

AU - Walker, Logan C.

AU - Fredericksen, Zachary S.

AU - Wang, Xianshu

AU - Tarrell, Robert

AU - Pankratz, Vernon S.

AU - Lindor, Noralane M.

AU - Beesley, Jonathan

AU - Healey, Sue

AU - Chen, Xiaoqing

AU - Stoppa-Lyonnet, Dominique

AU - Tirapo, Carole

AU - Giraud, Sophie

AU - Mazoyer, Sylvie

AU - Muller, Danièle

AU - Fricker, Jean Pierre

AU - Delnatte, Capucine D.

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Engel, Christoph

AU - Schönbuchner, Ines

AU - Deissler, Helmut

AU - Meindl, Alfons

AU - Hogervorst, Frans B.

AU - Verheus, Martijn

AU - Hooning, Maartje J.

AU - van den Ouweland, Ans M.W.

AU - Nelen, Marcel R.

AU - Ausems, Margreet G.E.M.

AU - Aalfs, Cora M.

AU - van Asperen, Christi J.

AU - Devilee, Peter

AU - Gerrits, Monique M.

AU - Waisfisz, Quinten

AU - Szabo, Csilla I.

AU - Easton, Douglas F.

AU - Peock, Susan

AU - Cook, Margaret

AU - Oliver, Clare T.

AU - Frost, Debra

AU - Harrington, Patricia

AU - Evans, D. Gareth

AU - Lalloo, Fiona

AU - Eeles, Ros

AU - Izatt, Louise

AU - Chu, Carol

AU - Davidson, Rosemarie

AU - Eccles, Diana

AU - Ong, Kai Ren

AU - Cook, Jackie

AU - Rebbeck, Tim

AU - Nathanson, Katherine L.

AU - Domchek, Susan M.

AU - Singer, Christian F.

AU - Gschwantler-Kaulich, Daphne

AU - Dressler, Anne Catharina

AU - Pfeiler, Georg

AU - Godwin, Andrew K.

AU - Heikkinen, Tuomas

AU - Nevanlinna, Heli

AU - Agnarsson, Bjarni A.

AU - Caligo, Maria A.

AU - Olsson, Håkan

AU - Kristoffersson, Ulf

AU - Liljegren, Annelie

AU - Arver, Brita

AU - Karlsson, Per

AU - Melin, Beatrice

AU - Sinilnikova, Olga M.

AU - McGuffog, Lesley

AU - Antoniou, Antonis C.

AU - Chenevix-Trench, Georgia

AU - Spurdle, Amanda B.

AU - Couch, Fergus J.

N1 - Funding Information: GC-HBOC is supported by a grant of the German Cancer Aid (grant107054) to RKS. The authors thank Juliane Köhler for her excellent technical assistance and the centres of the GC-HBOC for providing samples and clinical data. The HEBCS study was supported by Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. The authors thank Dr Kristiina Aittomäki, Dr Carl Blomqvist and Dr Kirsimari Aaltonen as well as RN Hanna Jäntti for their help with patient data and samples. The Pisa Breast Cancer Study (PBCS) acknowledges Fondazione Cassa di Risparmio di Pisa, Istituto Toscano Tumori. The Fox Chase Cancer Center (FCCC) acknowledges Ms JoEllen Weaver, Mr John Malick and Dr Betsy Bove for expert technical assistance. AKG was funded by SPORE P50 CA83638, U01 CA69631, 5U01 CA113916, and the Eileen Stein Jacoby Fund. The Medical University of Vienna (MUV) collaborators include CF Singer, D Gschwantler-Kaulich, G Pfeiler, and A-C Spiess. This research project has been supported by the Austrian Society for Endocrinological Oncology and by the Comprehensive Cancer Center, Cluster Genetics and Epigenetics. Georgetown acknowledges Claudine Isaacs and is supported by a National Cancer Institute Cancer Centre Support Grant to the Lombardi Comprehensive Cancer Centre (NCI P30 CA51008-12), Georgetown University, Washington, DC, USA. LCW is a John Gavin Postdoctoral Fellow (Genesis Oncology Trust), ABS is an NHMRC Senior Research Fellow, and GCT is an NHMRC Senior Principal Research Fellow. ACA is a Cancer Research UK Senior Cancer Research Fellow, and LM, the CIMBA genotyping and data management are funded by Cancer Research - UK.

PY - 2010/11/29

Y1 - 2010/11/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78649372135&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649372135&partnerID=8YFLogxK

U2 - 10.1186/bcr2785

DO - 10.1186/bcr2785

M3 - Article

C2 - 21114847

AN - SCOPUS:78649372135

SN - 1465-5411

VL - 12

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 6

M1 - R102

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this