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 & 66 others 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

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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.

Original languageEnglish
Pages (from-to)937-948
Number of pages12
JournalAmerican Journal of Human Genetics
Volume82
Issue number4
DOIs
StatePublished - Apr 11 2008

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Alleles
Breast Neoplasms
Mutation
Single Nucleotide Polymorphism
Germ-Line Mutation
Genome-Wide Association Study
Population

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., ... 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

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. / Antoniou, Antonis C.; Spurdle, Amanda B.; Sinilnikova, Olga M.; Healey, Sue; Pooley, Karen A.; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Arnold, Norbert; Hofmann, Wera; Sutter, Christian; Niederacher, Dieter; Deissler, Helmut; Caldes, Trinidad; Kämpjärvi, Kati; Nevanlinna, Heli; Simard, Jacques; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L.; Rebbeck, Timothy R.; Wagner, Theresa; Lynch, Henry T.; Isaacs, Claudine; Weitzel, Jeffrey; Ganz, Patricia A.; Daly, Mary B.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Blum, Joanne L.; Couch, Fergus J.; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Radice, Paolo; Szabo, Csilla I.; Pereira, Lutecia H Mateus; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Barnett-Griness, Ofra; Andrulis, Irene L.; Ozcelik, Hilmi; Gerdes, Anne Marie; Caligo, Maria A.; Laitman, Yael; Kaufman, Bella; Milgrom, Roni; Friedman, Eitan; Domchek, Susan M.; Nathanson, Katherine L.; Osorio, Ana; Llort, Gemma; Milne, Roger L.; Benítez, Javier; Hamann, Ute; Hogervorst, Frans B L; Manders, Peggy; Ligtenberg, Marjolijn J L; van den Ouweland, Ans M W; Peock, Susan; Cook, Margaret; Platte, Radka; Evans, D. Gareth; Eeles, Rosalind; Pichert, Gabriella; Chu, Carol; Eccles, Diana; Davidson, Rosemarie; Douglas, Fiona; Godwin, Andrew K.; Barjhoux, Laure; Mazoyer, Sylvie; Sobol, Hagay; Bourdon, Violaine; Eisinger, François; Chompret, Agnès; Capoulade, Corinne; Bressac-de Paillerets, Brigitte; Lenoir, Gilbert M.; Gauthier-Villars, Marion; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.

In: American Journal of Human Genetics, Vol. 82, No. 4, 11.04.2008, p. 937-948.

Research output: Contribution to journalArticle

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
Antoniou, Antonis C. ; Spurdle, Amanda B. ; Sinilnikova, Olga M. ; Healey, Sue ; Pooley, Karen A. ; Schmutzler, Rita K. ; Versmold, Beatrix ; Engel, Christoph ; Meindl, Alfons ; Arnold, Norbert ; Hofmann, Wera ; Sutter, Christian ; Niederacher, Dieter ; Deissler, Helmut ; Caldes, Trinidad ; Kämpjärvi, Kati ; Nevanlinna, Heli ; Simard, Jacques ; Beesley, Jonathan ; Chen, Xiaoqing ; Neuhausen, Susan L. ; Rebbeck, Timothy R. ; Wagner, Theresa ; Lynch, Henry T. ; Isaacs, Claudine ; Weitzel, Jeffrey ; Ganz, Patricia A. ; Daly, Mary B. ; Tomlinson, Gail ; Olopade, Olufunmilayo I. ; Blum, Joanne L. ; Couch, Fergus J. ; Peterlongo, Paolo ; Manoukian, Siranoush ; Barile, Monica ; Radice, Paolo ; Szabo, Csilla I. ; Pereira, Lutecia H Mateus ; Greene, Mark H. ; Rennert, Gad ; Lejbkowicz, Flavio ; Barnett-Griness, Ofra ; Andrulis, Irene L. ; Ozcelik, Hilmi ; Gerdes, Anne Marie ; Caligo, Maria A. ; Laitman, Yael ; Kaufman, Bella ; Milgrom, Roni ; Friedman, Eitan ; Domchek, Susan M. ; Nathanson, Katherine L. ; Osorio, Ana ; Llort, Gemma ; Milne, Roger L. ; Benítez, Javier ; Hamann, Ute ; Hogervorst, Frans B L ; Manders, Peggy ; Ligtenberg, Marjolijn J L ; van den Ouweland, Ans M W ; Peock, Susan ; Cook, Margaret ; Platte, Radka ; Evans, D. Gareth ; Eeles, Rosalind ; Pichert, Gabriella ; Chu, Carol ; Eccles, Diana ; Davidson, Rosemarie ; Douglas, Fiona ; Godwin, Andrew K. ; Barjhoux, Laure ; Mazoyer, Sylvie ; Sobol, Hagay ; Bourdon, Violaine ; Eisinger, François ; Chompret, Agnès ; Capoulade, Corinne ; Bressac-de Paillerets, Brigitte ; Lenoir, Gilbert M. ; Gauthier-Villars, Marion ; Houdayer, Claude ; Stoppa-Lyonnet, Dominique ; Chenevix-Trench, Georgia ; Easton, Douglas F. / Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. In: American Journal of Human Genetics. 2008 ; Vol. 82, No. 4. pp. 937-948.
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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.",
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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.

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