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; K. Con Fab; Dominique Stoppa-Lyonnet; Carole Tirapo; Sophie Giraud; Sylvie Mazoyer; Daniele Muller; Jean-Pierre Fricker; Capucine Delnatte; Rita K. Schmutzler; Barbara Wappenschmidt; Christoph Engel; Ines Schoenbuchner; 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; Mod S. Quad; 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

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, K. Con Fab, Dominique Stoppa-Lyonnet, Carole Tirapo, Sophie Giraud, Sylvie Mazoyer, Daniele Muller, Jean-Pierre Fricker, Capucine Delnatte, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph EngelInes Schoenbuchner, 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, Mod S. Quad, 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

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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 (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.

Original language	English
Journal	Breast Cancer Research
Volume	12
Issue number	6
DOIs	https://doi.org/10.1186/bcr2785
Publication status	Published - 2010

Subject classification (UKÄ)

Cancer and Oncology

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10.1186/bcr2785

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

@article{26ee0cb3824643bc9ae0fbe3e9e2c5b2,

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 (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 Xianshu Wang and Robert Tarrell and Pankratz, {Vernon S.} and Lindor, {Noralane M.} and Jonathan Beesley and Sue Healey and Xiaoqing Chen and Fab, {K. Con} and Dominique Stoppa-Lyonnet and Carole Tirapo and Sophie Giraud and Sylvie Mazoyer and Daniele Muller and Jean-Pierre Fricker and Capucine Delnatte and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Christoph Engel and Ines Schoenbuchner 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 Quad, {Mod S.} 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 Kai-Ren Ong and Jackie Cook and Tim Rebbeck and Nathanson, {Katherine L.} and Domchek, {Susan M.} and Singer, {Christian F.} and Daphne Gschwantler-Kaulich and Anne-Catharina Dressler and Georg Pfeiler and Godwin, {Andrew K.} and Tuomas Heikkinen and Heli Nevanlinna and Agnarsson, {Bjarni A.} and Caligo, {Maria Adelaide} 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.}",

year = "2010",

doi = "10.1186/bcr2785",

language = "English",

volume = "12",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central (BMC)",

number = "6",

}

Walker, LC, Fredericksen, ZS, Wang, X, Tarrell, R, Pankratz, VS, Lindor, NM, Beesley, J, Healey, S, Chen, X, Fab, KC, Stoppa-Lyonnet, D, Tirapo, C, Giraud, S, Mazoyer, S, Muller, D, Fricker, J-P, Delnatte, C, Schmutzler, RK, Wappenschmidt, B, Engel, C, Schoenbuchner, 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, Quad, MS, 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, K-R, Cook, J, Rebbeck, T, Nathanson, KL, Domchek, SM, Singer, CF, Gschwantler-Kaulich, D, Dressler, A-C, 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. https://doi.org/10.1186/bcr2785

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 - Fab, K. Con

AU - Stoppa-Lyonnet, Dominique

AU - Tirapo, Carole

AU - Giraud, Sophie

AU - Mazoyer, Sylvie

AU - Muller, Daniele

AU - Fricker, Jean-Pierre

AU - Delnatte, Capucine

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Engel, Christoph

AU - Schoenbuchner, 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 - Quad, Mod S.

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 Adelaide

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.

PY - 2010

Y1 - 2010

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 (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.

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 (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.

U2 - 10.1186/bcr2785

DO - 10.1186/bcr2785

M3 - Article

C2 - 21114847

VL - 12

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 6

ER -

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

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