Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Antonis C. Antoniou; Amanda B. Spurdle; Olga M. Sinilnikova; Sue Healey; Karen A. Pooley; Rita K. Schmutzler; Beatrix Versmold; Christoph Engel; Alfons Meindl; Norbert Arnold; Wera Hofmann; Christian Sutter; Dieter Niederacher; Helmut Deissler; Trinidad Caldes; Kati Kämpjärvi; Heli Nevanlinna; Jacques Simard; Jonathan Beesley; Xiaoqing Chen; Susan L. Neuhausen; Timothy R. Rebbeck; Theresa Wagner; Henry T. Lynch; Claudine Isaacs; Jeffrey Weitzel; Patricia A. Ganz; Mary B. Daly; Gail Tomlinson; Olufunmilayo I. Olopade; Joanne L. Blum; Fergus J. Couch; Paolo Peterlongo; Siranoush Manoukian; Monica Barile; Paolo Radice; Csilla I. Szabo; Lutecia H.Mateus Pereira; Mark H. Greene; Gad Rennert; Flavio Lejbkowicz; Ofra Barnett-Griness; Irene L. Andrulis; Hilmi Ozcelik; Anne Marie Gerdes; Maria A. Caligo; Yael Laitman; Bella Kaufman; Roni Milgrom; Eitan Friedman; Susan M. Domchek; Katherine L. Nathanson; Ana Osorio; Gemma Llort; Roger L. Milne; Javier Benítez; Ute Hamann; Frans B.L. Hogervorst; Peggy Manders; Marjolijn J.L. Ligtenberg; Ans M.W. van den Ouweland; Susan Peock; Margaret Cook; Radka Platte; D. Gareth Evans; Rosalind Eeles; Gabriella Pichert; Carol Chu; Diana Eccles; Rosemarie Davidson; Fiona Douglas; Andrew K. Godwin; Laure Barjhoux; Sylvie Mazoyer; Hagay Sobol; Violaine Bourdon; François Eisinger; Agnès Chompret; Corinne Capoulade; Brigitte Bressac-de Paillerets; Gilbert M. Lenoir; Marion Gauthier-Villars; Claude Houdayer; Dominique Stoppa-Lyonnet; Georgia Chenevix-Trench; Douglas F. Easton

doi:10.1016/j.ajhg.2008.02.008

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Antonis C. Antoniou
, Amanda B. Spurdle
, Olga M. Sinilnikova
, Sue Healey
, Karen A. Pooley
, Rita K. Schmutzler
, Beatrix Versmold
, Christoph Engel
, Alfons Meindl
, Norbert Arnold
, Wera Hofmann
, Christian Sutter
, Dieter Niederacher
, Helmut Deissler
, Trinidad Caldes
, Kati Kämpjärvi
, Heli Nevanlinna
, Jacques Simard
, Jonathan Beesley
, Xiaoqing Chen

Susan L. Neuhausen, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Claudine Isaacs, Jeffrey Weitzel, Patricia A. Ganz, Mary B. Daly, Gail Tomlinson, Olufunmilayo I. Olopade, Joanne L. Blum, Fergus J. Couch, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Paolo Radice, Csilla I. Szabo, Lutecia H.Mateus Pereira, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Ofra Barnett-Griness, Irene L. Andrulis, Hilmi Ozcelik, Anne Marie Gerdes, Maria A. Caligo, Yael Laitman, Bella Kaufman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Gemma Llort, Roger L. Milne, Javier Benítez, Ute Hamann, Frans B.L. Hogervorst, Peggy Manders, Marjolijn J.L. Ligtenberg, Ans M.W. van den Ouweland, Susan Peock, Margaret Cook, Radka Platte, D. Gareth Evans, Rosalind Eeles, Gabriella Pichert, Carol Chu, Diana Eccles, Rosemarie Davidson, Fiona Douglas, Andrew K. Godwin, Laure Barjhoux, Sylvie Mazoyer, Hagay Sobol, Violaine Bourdon, François Eisinger, Agnès Chompret, Corinne Capoulade, Brigitte Bressac-de Paillerets, Gilbert M. Lenoir, Marion Gauthier-Villars, Claude Houdayer, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F. Easton

Cancer Research UK Program
Peter Maccallum Cancer Centre
Queensland Institute of Medical Research
Centre de Recherche en Cancérologie de Lyon
Universite Claude Bernard Lyon 1
University of Cologne
Leipzig University
Technical University of Munich
Kiel University
Charité – Universitätsmedizin Berlin
Heidelberg University
Heinrich Heine University Düsseldorf
Ulm University
Hospital Clínico San Carlos de Madrid
Helsinki University Hospital
Université Laval
University of California at Irvine
University of Pennsylvania
University of Vienna
Creighton University
Georgetown University
City of Hope National Medical Center
University of California at Los Angeles
University of Texas at Dallas
University of Chicago
Baylor Health Care System
Mayo Clinic
Fondazione IRCCS Istituto Nazionale dei Tumori
IRCCS Istituto Europeo di Oncologia - Milano
Mayo Clinic College of Medicine and Science
National Institutes of Health
Clalit Health Services
Cancer Care Ontario
University of Toronto
University of Southern Denmark
University of Pisa
The Gertner Institute
Sheba Medical Center at Tel Hashomer
Biomedical Network on Rare Diseases (CIBERER)
Institute Catala Oncologia
German Cancer Research Center
Netherlands Cancer Institute
Radboud University Nijmegen
Erasmus University Rotterdam
Imperial College Healthcare NHS Trust
Royal Marsden Hospital
King's College London
Yorkshire Regional Genetics Service
University Hospital Southampton NHS Foundation Trust
Ferguson-Smith Centre for Clinical Genetics
Centre for Life
Fox Chase Cancer Center
Institut national de la santé et de la recherche médicale
Université Paris-Sud
Institut Curie

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

252 Scopus citations

Abstract

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p_trend = 1.7 × 10^-8 and HR = 1.12, 95% CI: 1.02-1.24, p_trend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p_trend = 5 × 10^-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Original language	English
Pages (from-to)	937-948
Number of pages	12
Journal	American Journal of Human Genetics
Volume	82
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2008.02.008
State	Published - Apr 11 2008

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adult
Aged
Breast Neoplasms/genetics
Female
Genes, BRCA1
Genes, BRCA2
Genetic Predisposition to Disease/genetics
Germ-Line Mutation
Humans
MAP Kinase Kinase Kinase 1/genetics
Middle Aged
Polymorphism, Single Nucleotide
Receptor, Fibroblast Growth Factor, Type 2/genetics
Risk

Access to Document

10.1016/j.ajhg.2008.02.008

Cite this

Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., Niederacher, D., Deissler, H., Caldes, T., Kämpjärvi, K., Nevanlinna, H., Simard, J., Beesley, J., ... Easton, D. F. (2008). Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. American Journal of Human Genetics, 82(4), 937-948. https://doi.org/10.1016/j.ajhg.2008.02.008

@article{1c9541b8f284445e819e6a7ed004dc0f,

title = "Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers",

abstract = "Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95\% CI: 1.20-1.45, ptrend = 1.7 × 10-8 and HR = 1.12, 95\% CI: 1.02-1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95\% CI: 1.06-1.20, ptrend = 5 × 10-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.",

keywords = "Adult, Aged, Breast Neoplasms/genetics, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease/genetics, Germ-Line Mutation, Humans, MAP Kinase Kinase Kinase 1/genetics, Middle Aged, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2/genetics, Risk",

author = "Antoniou, \{Antonis C.\} and Spurdle, \{Amanda B.\} and Sinilnikova, \{Olga M.\} and Sue Healey and Pooley, \{Karen A.\} and Schmutzler, \{Rita K.\} and Beatrix Versmold and Christoph Engel and Alfons Meindl and Norbert Arnold and Wera Hofmann and Christian Sutter and Dieter Niederacher and Helmut Deissler and Trinidad Caldes and Kati K{\"a}mpj{\"a}rvi and Heli Nevanlinna and Jacques Simard and Jonathan Beesley and Xiaoqing Chen and Neuhausen, \{Susan L.\} and Rebbeck, \{Timothy R.\} and Theresa Wagner and Lynch, \{Henry T.\} and Claudine Isaacs and Jeffrey Weitzel and Ganz, \{Patricia A.\} and Daly, \{Mary B.\} and Gail Tomlinson and Olopade, \{Olufunmilayo I.\} and Blum, \{Joanne L.\} and Couch, \{Fergus J.\} and Paolo Peterlongo and Siranoush Manoukian and Monica Barile and Paolo Radice and Szabo, \{Csilla I.\} and Pereira, \{Lutecia H.Mateus\} and Greene, \{Mark H.\} and Gad Rennert and Flavio Lejbkowicz and Ofra Barnett-Griness and Andrulis, \{Irene L.\} and Hilmi Ozcelik and Gerdes, \{Anne Marie\} and Caligo, \{Maria A.\} and Yael Laitman and Bella Kaufman and Roni Milgrom and Eitan Friedman and Domchek, \{Susan M.\} and Nathanson, \{Katherine L.\} and Ana Osorio and Gemma Llort and Milne, \{Roger L.\} and Javier Ben{\'i}tez and Ute Hamann and Hogervorst, \{Frans B.L.\} and Peggy Manders and Ligtenberg, \{Marjolijn J.L.\} and \{van den Ouweland\}, \{Ans M.W.\} and Susan Peock and Margaret Cook and Radka Platte and Evans, \{D. Gareth\} and Rosalind Eeles and Gabriella Pichert and Carol Chu and Diana Eccles and Rosemarie Davidson and Fiona Douglas and Godwin, \{Andrew K.\} and Laure Barjhoux and Sylvie Mazoyer and Hagay Sobol and Violaine Bourdon and Fran{\c c}ois Eisinger and Agn{\`e}s Chompret and Corinne Capoulade and \{Bressac-de Paillerets\}, Brigitte and Lenoir, \{Gilbert M.\} and Marion Gauthier-Villars and Claude Houdayer and Dominique Stoppa-Lyonnet and Georgia Chenevix-Trench and Easton, \{Douglas F.\}",

year = "2008",

month = apr,

day = "11",

doi = "10.1016/j.ajhg.2008.02.008",

language = "English",

volume = "82",

pages = "937--948",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

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, Kämpjärvi, 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, Blum, JL, Couch, FJ, Peterlongo, P, Manoukian, S, Barile, M, Radice, P, Szabo, CI, Pereira, LHM, Greene, MH, Rennert, G, Lejbkowicz, F, Barnett-Griness, O, Andrulis, IL, Ozcelik, H, Gerdes, AM, Caligo, MA, Laitman, Y, Kaufman, B, Milgrom, R, Friedman, E, Domchek, SM, Nathanson, KL, Osorio, A, Llort, G, Milne, RL, Benítez, J, Hamann, U, Hogervorst, FBL, Manders, P, Ligtenberg, MJL, van den Ouweland, AMW, Peock, S, Cook, M, Platte, R, Evans, DG, Eeles, R, Pichert, G, Chu, C, Eccles, D, Davidson, R, Douglas, F, Godwin, AK, Barjhoux, L, Mazoyer, S, Sobol, H, Bourdon, V, Eisinger, F, Chompret, A, Capoulade, C, Bressac-de Paillerets, B, Lenoir, GM, Gauthier-Villars, M, Houdayer, C, Stoppa-Lyonnet, D, Chenevix-Trench, G & Easton, DF 2008, 'Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers', American Journal of Human Genetics, vol. 82, no. 4, pp. 937-948. https://doi.org/10.1016/j.ajhg.2008.02.008

TY - JOUR

T1 - Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

AU - Antoniou, Antonis C.

AU - Spurdle, Amanda B.

AU - Sinilnikova, Olga M.

AU - Healey, Sue

AU - Pooley, Karen A.

AU - Schmutzler, Rita K.

AU - Versmold, Beatrix

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Arnold, Norbert

AU - Hofmann, Wera

AU - Sutter, Christian

AU - Niederacher, Dieter

AU - Deissler, Helmut

AU - Caldes, Trinidad

AU - Kämpjärvi, Kati

AU - Nevanlinna, Heli

AU - Simard, Jacques

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Neuhausen, Susan L.

AU - Rebbeck, Timothy R.

AU - Wagner, Theresa

AU - Lynch, Henry T.

AU - Isaacs, Claudine

AU - Weitzel, Jeffrey

AU - Ganz, Patricia A.

AU - Daly, Mary B.

AU - Tomlinson, Gail

AU - Olopade, Olufunmilayo I.

AU - Blum, Joanne L.

AU - Couch, Fergus J.

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Barile, Monica

AU - Radice, Paolo

AU - Szabo, Csilla I.

AU - Pereira, Lutecia H.Mateus

AU - Greene, Mark H.

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Barnett-Griness, Ofra

AU - Andrulis, Irene L.

AU - Ozcelik, Hilmi

AU - Gerdes, Anne Marie

AU - Caligo, Maria A.

AU - Laitman, Yael

AU - Kaufman, Bella

AU - Milgrom, Roni

AU - Friedman, Eitan

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Osorio, Ana

AU - Llort, Gemma

AU - Milne, Roger L.

AU - Benítez, Javier

AU - Hamann, Ute

AU - Hogervorst, Frans B.L.

AU - Manders, Peggy

AU - Ligtenberg, Marjolijn J.L.

AU - van den Ouweland, Ans M.W.

AU - Peock, Susan

AU - Cook, Margaret

AU - Platte, Radka

AU - Evans, D. Gareth

AU - Eeles, Rosalind

AU - Pichert, Gabriella

AU - Chu, Carol

AU - Eccles, Diana

AU - Davidson, Rosemarie

AU - Douglas, Fiona

AU - Godwin, Andrew K.

AU - Barjhoux, Laure

AU - Mazoyer, Sylvie

AU - Sobol, Hagay

AU - Bourdon, Violaine

AU - Eisinger, François

AU - Chompret, Agnès

AU - Capoulade, Corinne

AU - Bressac-de Paillerets, Brigitte

AU - Lenoir, Gilbert M.

AU - Gauthier-Villars, Marion

AU - Houdayer, Claude

AU - Stoppa-Lyonnet, Dominique

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

PY - 2008/4/11

Y1 - 2008/4/11

N2 - Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, ptrend = 1.7 × 10-8 and HR = 1.12, 95% CI: 1.02-1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, ptrend = 5 × 10-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

AB - Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, ptrend = 1.7 × 10-8 and HR = 1.12, 95% CI: 1.02-1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, ptrend = 5 × 10-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

KW - Adult

KW - Aged

KW - Breast Neoplasms/genetics

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease/genetics

KW - Germ-Line Mutation

KW - Humans

KW - MAP Kinase Kinase Kinase 1/genetics

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Receptor, Fibroblast Growth Factor, Type 2/genetics

KW - Risk

UR - https://www.scopus.com/pages/publications/41649097333

UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000255103900012&DestLinkType=FullRecord&DestApp=WOS

U2 - 10.1016/j.ajhg.2008.02.008

DO - 10.1016/j.ajhg.2008.02.008

M3 - Article

C2 - 18355772

SN - 0002-9297

VL - 82

SP - 937

EP - 948

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Abstract

UN SDGs

Keywords

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