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 Kampjarvi; 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. Bium; Fergus J. Couch; Paolo Peterlongo; Siranoush Manoukian; Monica Barile; Paolo Radice; Csilla I. Szabo; Lutecia H. Mateus Pereira; Mark H. Greene; Gad Rennert; Flavio Leibkowicz; Ofra Barnett-Griness; Irene L. Andrulis; Hilmi Ozcelik; Anne-Marie Gerdes; Maria A. Caligo; Yael Laitman; Bella Kaufman; Roni Milgrom; Eitan Friedman; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab); OCGN; Swedish BRCA1; DNA-HEBON Collaborators; EMBRACE; GEMO; CIMBA; Encarna B. Gomez Garcia

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 Kampjarvi, Heli Nevanlinna, Jacques Simard, Jonathan Beesley, Xiaoqing ChenSusan 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. Bium, Fergus J. Couch, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Paolo Radice, Csilla I. Szabo, Lutecia H. Mateus Pereira, Mark H. Greene, Gad Rennert, Flavio Leibkowicz, Ofra Barnett-Griness, Irene L. Andrulis, Hilmi Ozcelik, Anne-Marie Gerdes, Maria A. Caligo, Yael Laitman, Bella Kaufman, Roni Milgrom, Eitan Friedman, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), OCGN, Swedish BRCA1, DNA-HEBON Collaborators, EMBRACE, GEMO, CIMBA, Encarna B. Gomez Garcia

GROW - Research Institute for Oncology and Reproduction

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

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 x 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 x 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
Publication status	Published - Apr 2008

Keywords

Prophylactic oophorectomy
Genes
Investigators
Penetrance
Consortium
Modifiers
Model

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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., Kampjarvi, K., Nevanlinna, H., Simard, J., Beesley, J., ... Gomez Garcia, E. B. (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{36456d7cbc7d4ab1a2e76b880c2bd938,

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, p(trend) = 1.7 x 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 x 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 = "Prophylactic oophorectomy, Genes, Investigators, Penetrance, Consortium, Modifiers, Model",

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 Kampjarvi 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 Bium, {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 Leibkowicz and Ofra Barnett-Griness and Andrulis, {Irene L.} and Hilmi Ozcelik and Anne-Marie Gerdes and Caligo, {Maria A.} and Yael Laitman and Bella Kaufman and Roni Milgrom and Eitan Friedman and {Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)} and OCGN and {Swedish BRCA1} and {DNA-HEBON Collaborators} and EMBRACE and GEMO and CIMBA and {Gomez Garcia}, {Encarna B.}",

year = "2008",

month = apr,

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, 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, Bium, JL, Couch, FJ, Peterlongo, P, Manoukian, S, Barile, M, Radice, P, Szabo, CI, Pereira, LHM, Greene, MH, Rennert, G, Leibkowicz, F, Barnett-Griness, O, Andrulis, IL, Ozcelik, H, Gerdes, A-M, Caligo, MA, Laitman, Y, Kaufman, B, Milgrom, R, Friedman, E, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), OCGN, Swedish BRCA1, DNA-HEBON Collaborators, EMBRACE, GEMO, CIMBA & Gomez Garcia, EB 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 - Kampjarvi, 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 - Bium, 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 - Leibkowicz, 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 - Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)

AU - OCGN

AU - Swedish BRCA1

AU - DNA-HEBON Collaborators

AU - EMBRACE

AU - GEMO

AU - CIMBA

AU - Gomez Garcia, Encarna B.

PY - 2008/4

Y1 - 2008/4

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, p(trend) = 1.7 x 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 x 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, p(trend) = 1.7 x 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 x 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 - Prophylactic oophorectomy

KW - Genes

KW - Investigators

KW - Penetrance

KW - Consortium

KW - Modifiers

KW - Model

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 <i>BRCA</i>1 and <i>BRC</i>A2 mutation carriers

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Keywords

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