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Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
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
breast, risk, mutations, cell, brca2, brca1, tumors, breast cancer, prophylactic oophorectomy, penetrance, germline mutations, cancer, single nucleotide polymorphism, model, consortium, modifiers, breast-cancer, genes, investigators
0002-9297
937-948
Antoniou, A.C.
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Spurdle, A.B.
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Sinilnikova, O.M.
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Healey, S.
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Pooley, K.A.
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Schmutzler, R.K.
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Versmold, B.
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Deissler, H.
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Eccles, D.
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Eisinger, F.
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Houdayer, C.
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Antoniou, A.C.
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Spurdle, A.B.
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Sinilnikova, O.M.
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Healey, S.
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Schmutzler, R.K.
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Versmold, B.
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Meindl, A.
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Caldes, T.
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Caligo, M.A.
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Kaufman, B.
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Milgrom, R.
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Manders, P.
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Cook, M.
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Eeles, R.
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Eccles, D.
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Bourdon, V.
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Capoulade, C.
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Paillerets, B.B.D.
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Lenoir, G.M.
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Houdayer, C.
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Easton, D.F.
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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., Chen, X.Q., Neuhausen, S.L., Rebbeck, T.R., Wagner, T., Lynch, H.T., Isaacs, C., Weitzel, J., Ganz, P.A., Daly, M.B., Tomlinson, G., Olopade, O.I., Bium, J.L., Couch, F. J., Peterlongo, P., Manoukian, S., Barile, M., Radice, P., Szabo, C.I., Pereira, L.H.M., Greene, M.H., Rennert, G., Leibkowicz, F., Barnett-Griness, O., Andrulis, I.L., Ozcelik, H., Gerdes, A.M., Caligo, M.A., Laitman, Y., Kaufman, B., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Osorio, A., Llort, G., Milne, R.L., Benitez, J., Hamann, U., Hogervorst, F.B.L., Manders, P., Ligtenberg, M.J.L., Van den, A.M.W., Peock, S., Cook, M., Platte, R., Evans, D.G., Eeles, R., Pichert, G., Chu, C., Eccles, D., Davidson, R., Douglas, F., Godwin, A.K., Barjhoux, L., Mazoyer, S., Sobol, H., Bourdon, V., Eisinger, F., Chompret, A., Capoulade, C., Paillerets, B.B.D., Lenoir, G.M., Gauthier-Villars, M., Houdayer, C., Stoppa-Lyonnet, D. and 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. (doi:10.1016/j.ajhg.2008.02.008).

Record type: Article

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

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More information

Published date: 2008
Keywords: breast, risk, mutations, cell, brca2, brca1, tumors, breast cancer, prophylactic oophorectomy, penetrance, germline mutations, cancer, single nucleotide polymorphism, model, consortium, modifiers, breast-cancer, genes, investigators

Identifiers

Local EPrints ID: 62674
URI: http://eprints.soton.ac.uk/id/eprint/62674
DOI: doi:10.1016/j.ajhg.2008.02.008
ISSN: 0002-9297
PURE UUID: 3ab6154b-eaa4-4bc5-b351-62ef0bd6b90c
ORCID for D. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 03 Sep 2008
Last modified: 16 Mar 2024 02:39

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Contributors

Author: A.C. Antoniou
Author: A.B. Spurdle
Author: O.M. Sinilnikova
Author: S. Healey
Author: K.A. Pooley
Author: R.K. Schmutzler
Author: B. Versmold
Author: C. Engel
Author: A. Meindl
Author: N. Arnold
Author: W. Hofmann
Author: C. Sutter
Author: D. Niederacher
Author: H. Deissler
Author: T. Caldes
Author: K. Kampjarvi
Author: H. Nevanlinna
Author: J. Simard
Author: J. Beesley
Author: X.Q. Chen
Author: S.L. Neuhausen
Author: T.R. Rebbeck
Author: T. Wagner
Author: H.T. Lynch
Author: C. Isaacs
Author: J. Weitzel
Author: P.A. Ganz
Author: M.B. Daly
Author: G. Tomlinson
Author: O.I. Olopade
Author: J.L. Bium
Author: F. J. Couch
Author: P. Peterlongo
Author: S. Manoukian
Author: M. Barile
Author: P. Radice
Author: C.I. Szabo
Author: L.H.M. Pereira
Author: M.H. Greene
Author: G. Rennert
Author: F. Leibkowicz
Author: O. Barnett-Griness
Author: I.L. Andrulis
Author: H. Ozcelik
Author: A.M. Gerdes
Author: M.A. Caligo
Author: Y. Laitman
Author: B. Kaufman
Author: R. Milgrom
Author: E. Friedman
Author: S.M. Domchek
Author: K.L. Nathanson
Author: A. Osorio
Author: G. Llort
Author: R.L. Milne
Author: J. Benitez
Author: U. Hamann
Author: F.B.L. Hogervorst
Author: P. Manders
Author: M.J.L. Ligtenberg
Author: A.M.W. Van den
Author: S. Peock
Author: M. Cook
Author: R. Platte
Author: D.G. Evans
Author: R. Eeles
Author: G. Pichert
Author: C. Chu
Author: D. Eccles ORCID iD
Author: R. Davidson
Author: F. Douglas
Author: A.K. Godwin
Author: L. Barjhoux
Author: S. Mazoyer
Author: H. Sobol
Author: V. Bourdon
Author: F. Eisinger
Author: A. Chompret
Author: C. Capoulade
Author: B.B.D. Paillerets
Author: G.M. Lenoir
Author: M. Gauthier-Villars
Author: C. Houdayer
Author: D. Stoppa-Lyonnet
Author: D.F. Easton

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