Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Antonis C. Antoniou; Jonathan Beesley; Lesley McGuffog; Olga M. Sinilnikova; Sue Healey; Susan L. Neuhausen; Yuan Chun Ding; Timothy R. Rebbeck; Jeffrey N. Weitzel; Henry T. Lynch; Claudine Isaacs; Patricia A. Ganz; Gail E. Tomlinson; Olufunmilayo I. Olopade; Fergus J. Couch; Xianshu Wang; Noralane M. Lindor; Vernon S. Pankratz; Paolo Radice; Siranoush Manoukian; Bernard Peissel; Daniela Zaffaroni; Monica Barile; Alessandra Viel; Anna Allavena; Valentina Dall'Olio; Paolo Peterlongo; Csilla I. Szabo; Michal Zikan; Kathleen Claes; Bruce Poppe; Lenka Foretova; Phuong L. Mai; Mark H. Greene; Gad Rennert; Flavio Lejbkowicz; Gord Glendon; Hilmi Ozcelik; Irene L. Andrulis; Mads Thomassen; Anne-Marie Gerdes; Lone Sunde; Dorthe Cruger; Uffe Birk Jensen; Maria A. Caligo; Eitan Friedman; Bella Kaufman; Yael Laitman; Roni Milgrom; Maya Dubrovsky; Shimrit Cohen; Ake Borg; Helena Jernstroem; Annika Lindblom; Johanna Rantala; Marie Stenmark-Askmalm; Beatrice Melin; Kate Nathanson; Susan Domchek; Ania Jakubowska; Jan Lubinski; Tomasz Huzarski; Ana Osorio; Adriana Lasa; Mercedes Duran; Maria-Isabel Tejada; Javier Godino; Javier Benitez; Ute Hamann; Mieke Kriege; Nicoline Hoogerbrugge; Rob B. van der Luijt; Christi J. van Asperen; Peter Devilee; Hanne E. J. Meijers-Heijboer; Marinus J. Blok; Cora M. Aalfs; Frans B. L. Hogervorst; Matti A. Rookus; Margaret Cook; Clare Oliver; Debra Frost; Don Conroy; D. Gareth Evans; Fiona Lalloo; Gabriella Pichert; Rosemarie Davidson; Trevor Cole; Jackie Cook; Joan Paterson; Shirley V. Hodgson; Patrick J. Morrison; Mary E. Porteous; Lisa Walker; M. John Kennedy; Huw Dorkins; Susan Peock; Andrew K. Godwin; Dominique Stoppa-Lyonnet; Antoine de Pauw; Sylvie Mazoyer; Valerie Bonadona; Christine Lasset; Helene Dreyfus; Dominique Leroux; Agnes Hardouin; Pascaline Berthet; Laurence Faivre; Catherine Loustalot; Tetsuro Noguchi; Hagay Sobol; Etienne Rouleau; Catherine Nogues; Marc Frenay; Laurence Venat-Bouvet; John L. Hopper; Mary B. Daly; Mary Beth Terry; Esther M. John; Saundra Buys; Yosuf Yassin; Alexander Miron; David E. Goldgar; Christian F. Singer; Anne Catharina Dressler; Daphne Gschwantler-Kaulich; Georg Pfeiler; Thomas V. O. Hansen; Lars Jnson; Bjarni A. Agnarsson; Tomas Kirchhoff; Kenneth Offit; Vincent Devlin; Ana Dutra-Clarke; Marion Piedmonte; Gustavo C. Rodriguez; Katie Wakeley; John F. Boggess; Jack Basil; Peter E. Schwartz; Stephanie V. Blank; Amanda Ewart Toland; Marco Montagna; Cinzia Casella; Evgeny N. Imyanitov; Laima Tihomirova; Ignacio Blanco; Conxi Lazaro; Susan J. Ramus; Lara Sucheston; Beth Y. Karlan; Jenny Gross; Rita Schmutzler; Barbara Wappenschmidt; Christoph Engel; Alfons Meindl; Magdalena Lochmann; Norbert Arnold; Simone Heidemann; Raymonda Varon-Mateeva; Dieter Niederacher; Christian Sutter; Helmut Deissler; Dorothea Gadzicki; Sabine Preisler-Adams; Karin Kast; Ines Schoenbuchner; Trinidad Caldes; Miguel De La Hoya; Kristiina Aittomaeki; Heli Nevanlinna; Jacques Simard; Amanda B. Spurdle; Helene Holland; Xiaoqing Chen; Radka Platte; Georgia Chenevix-Trench; Douglas F. Easton

doi:10.1158/0008-5472.CAN-10-1907

Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Antonis C. Antoniou^*, Jonathan Beesley, Lesley McGuffog, Olga M. Sinilnikova, Sue Healey, Susan L. Neuhausen, Yuan Chun Ding, Timothy R. Rebbeck, Jeffrey N. Weitzel, Henry T. Lynch, Claudine Isaacs, Patricia A. Ganz, Gail E. Tomlinson, Olufunmilayo I. Olopade, Fergus J. Couch, Xianshu Wang, Noralane M. Lindor, Vernon S. Pankratz, Paolo Radice, Siranoush ManoukianBernard Peissel, Daniela Zaffaroni, Monica Barile, Alessandra Viel, Anna Allavena, Valentina Dall'Olio, Paolo Peterlongo, Csilla I. Szabo, Michal Zikan, Kathleen Claes, Bruce Poppe, Lenka Foretova, Phuong L. Mai, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Gord Glendon, Hilmi Ozcelik, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Lone Sunde, Dorthe Cruger, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Maya Dubrovsky, Shimrit Cohen, Ake Borg, Helena Jernstroem, Annika Lindblom, Johanna Rantala, Marie Stenmark-Askmalm, Beatrice Melin, Kate Nathanson, Susan Domchek, Ania Jakubowska, Jan Lubinski, Tomasz Huzarski, Ana Osorio, Adriana Lasa, Mercedes Duran, Maria-Isabel Tejada, Javier Godino, Javier Benitez, Ute Hamann, Mieke Kriege, Nicoline Hoogerbrugge, Rob B. van der Luijt, Christi J. van Asperen, Peter Devilee, Hanne E. J. Meijers-Heijboer, Marinus J. Blok, Cora M. Aalfs, Frans B. L. Hogervorst, Matti A. Rookus, Margaret Cook, Clare Oliver, Debra Frost, Don Conroy, D. Gareth Evans, Fiona Lalloo, Gabriella Pichert, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Shirley V. Hodgson, Patrick J. Morrison, Mary E. Porteous, Lisa Walker, M. John Kennedy, Huw Dorkins, Susan Peock, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Antoine de Pauw, Sylvie Mazoyer, Valerie Bonadona, Christine Lasset, Helene Dreyfus, Dominique Leroux, Agnes Hardouin, Pascaline Berthet, Laurence Faivre, Catherine Loustalot, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Nogues, Marc Frenay, Laurence Venat-Bouvet, John L. Hopper, Mary B. Daly, Mary Beth Terry, Esther M. John, Saundra Buys, Yosuf Yassin, Alexander Miron, David E. Goldgar, Christian F. Singer, Anne Catharina Dressler, Daphne Gschwantler-Kaulich, Georg Pfeiler, Thomas V. O. Hansen, Lars Jnson, Bjarni A. Agnarsson, Tomas Kirchhoff, Kenneth Offit, Vincent Devlin, Ana Dutra-Clarke, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank, Amanda Ewart Toland, Marco Montagna, Cinzia Casella, Evgeny N. Imyanitov, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Susan J. Ramus, Lara Sucheston, Beth Y. Karlan, Jenny Gross, Rita Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Magdalena Lochmann, Norbert Arnold, Simone Heidemann, Raymonda Varon-Mateeva, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Sabine Preisler-Adams, Karin Kast, Ines Schoenbuchner, Trinidad Caldes, Miguel De La Hoya, Kristiina Aittomaeki, Heli Nevanlinna, Jacques Simard, Amanda B. Spurdle, Helene Holland, Xiaoqing Chen, Radka Platte, Georgia Chenevix-Trench, Douglas F. Easton

^*Corresponding author for this work

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

Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 ? 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

Original language	English
Pages (from-to)	9742-9754
Journal	Cancer Research
Volume	70
Issue number	23
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-1907
Publication status	Published - 1 Dec 2010

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10.1158/0008-5472.CAN-10-1907

Cite this

Antoniou, A. C., Beesley, J., McGuffog, L., Sinilnikova, O. M., Healey, S., Neuhausen, S. L., Ding, Y. C., Rebbeck, T. R., Weitzel, J. N., Lynch, H. T., Isaacs, C., Ganz, P. A., Tomlinson, G. E., Olopade, O. I., Couch, F. J., Wang, X., Lindor, N. M., Pankratz, V. S., Radice, P., ... Easton, D. F. (2010). Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction. Cancer Research, 70(23), 9742-9754. https://doi.org/10.1158/0008-5472.CAN-10-1907

@article{1837bcfc7fce4708989780f5466b34e5,

title = "Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction",

abstract = "The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 ? 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.",

author = "Antoniou, {Antonis C.} and Jonathan Beesley and Lesley McGuffog and Sinilnikova, {Olga M.} and Sue Healey and Neuhausen, {Susan L.} and Ding, {Yuan Chun} and Rebbeck, {Timothy R.} and Weitzel, {Jeffrey N.} and Lynch, {Henry T.} and Claudine Isaacs and Ganz, {Patricia A.} and Tomlinson, {Gail E.} and Olopade, {Olufunmilayo I.} and Couch, {Fergus J.} and Xianshu Wang and Lindor, {Noralane M.} and Pankratz, {Vernon S.} and Paolo Radice and Siranoush Manoukian and Bernard Peissel and Daniela Zaffaroni and Monica Barile and Alessandra Viel and Anna Allavena and Valentina Dall'Olio and Paolo Peterlongo and Szabo, {Csilla I.} and Michal Zikan and Kathleen Claes and Bruce Poppe and Lenka Foretova and Mai, {Phuong L.} and Greene, {Mark H.} and Gad Rennert and Flavio Lejbkowicz and Gord Glendon and Hilmi Ozcelik and Andrulis, {Irene L.} and Mads Thomassen and Anne-Marie Gerdes and Lone Sunde and Dorthe Cruger and Jensen, {Uffe Birk} and Caligo, {Maria A.} and Eitan Friedman and Bella Kaufman and Yael Laitman and Roni Milgrom and Maya Dubrovsky and Shimrit Cohen and Ake Borg and Helena Jernstroem and Annika Lindblom and Johanna Rantala and Marie Stenmark-Askmalm and Beatrice Melin and Kate Nathanson and Susan Domchek and Ania Jakubowska and Jan Lubinski and Tomasz Huzarski and Ana Osorio and Adriana Lasa and Mercedes Duran and Maria-Isabel Tejada and Javier Godino and Javier Benitez and Ute Hamann and Mieke Kriege and Nicoline Hoogerbrugge and {van der Luijt}, {Rob B.} and {van Asperen}, {Christi J.} and Peter Devilee and Meijers-Heijboer, {Hanne E. J.} and Blok, {Marinus J.} and Aalfs, {Cora M.} and Hogervorst, {Frans B. L.} and Rookus, {Matti A.} and Margaret Cook and Clare Oliver and Debra Frost and Don Conroy and Evans, {D. Gareth} and Fiona Lalloo and Gabriella Pichert and Rosemarie Davidson and Trevor Cole and Jackie Cook and Joan Paterson and Hodgson, {Shirley V.} and Morrison, {Patrick J.} and Porteous, {Mary E.} and Lisa Walker and Kennedy, {M. John} and Huw Dorkins and Susan Peock and Godwin, {Andrew K.} and Dominique Stoppa-Lyonnet and {de Pauw}, Antoine and Sylvie Mazoyer and Valerie Bonadona and Christine Lasset and Helene Dreyfus and Dominique Leroux and Agnes Hardouin and Pascaline Berthet and Laurence Faivre and Catherine Loustalot and Tetsuro Noguchi and Hagay Sobol and Etienne Rouleau and Catherine Nogues and Marc Frenay and Laurence Venat-Bouvet and Hopper, {John L.} and Daly, {Mary B.} and Terry, {Mary Beth} and John, {Esther M.} and Saundra Buys and Yosuf Yassin and Alexander Miron and Goldgar, {David E.} and Singer, {Christian F.} and Dressler, {Anne Catharina} and Daphne Gschwantler-Kaulich and Georg Pfeiler and Hansen, {Thomas V. O.} and Lars Jnson and Agnarsson, {Bjarni A.} and Tomas Kirchhoff and Kenneth Offit and Vincent Devlin and Ana Dutra-Clarke and Marion Piedmonte and Rodriguez, {Gustavo C.} and Katie Wakeley and Boggess, {John F.} and Jack Basil and Schwartz, {Peter E.} and Blank, {Stephanie V.} and Toland, {Amanda Ewart} and Marco Montagna and Cinzia Casella and Imyanitov, {Evgeny N.} and Laima Tihomirova and Ignacio Blanco and Conxi Lazaro and Ramus, {Susan J.} and Lara Sucheston and Karlan, {Beth Y.} and Jenny Gross and Rita Schmutzler and Barbara Wappenschmidt and Christoph Engel and Alfons Meindl and Magdalena Lochmann and Norbert Arnold and Simone Heidemann and Raymonda Varon-Mateeva and Dieter Niederacher and Christian Sutter and Helmut Deissler and Dorothea Gadzicki and Sabine Preisler-Adams and Karin Kast and Ines Schoenbuchner and Trinidad Caldes and {De La Hoya}, Miguel and Kristiina Aittomaeki and Heli Nevanlinna and Jacques Simard and Spurdle, {Amanda B.} and Helene Holland and Xiaoqing Chen and Radka Platte and Georgia Chenevix-Trench and Easton, {Douglas F.}",

year = "2010",

month = dec,

day = "1",

doi = "10.1158/0008-5472.CAN-10-1907",

language = "English",

volume = "70",

pages = "9742--9754",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "23",

}

Antoniou, AC, Beesley, J, McGuffog, L, Sinilnikova, OM, Healey, S, Neuhausen, SL, Ding, YC, Rebbeck, TR, Weitzel, JN, Lynch, HT, Isaacs, C, Ganz, PA, Tomlinson, GE, Olopade, OI, Couch, FJ, Wang, X, Lindor, NM, Pankratz, VS, Radice, P, Manoukian, S, Peissel, B, Zaffaroni, D, Barile, M, Viel, A, Allavena, A, Dall'Olio, V, Peterlongo, P, Szabo, CI, Zikan, M, Claes, K, Poppe, B, Foretova, L, Mai, PL, Greene, MH, Rennert, G, Lejbkowicz, F, Glendon, G, Ozcelik, H, Andrulis, IL, Thomassen, M, Gerdes, A-M, Sunde, L, Cruger, D, Jensen, UB, Caligo, MA, Friedman, E, Kaufman, B, Laitman, Y, Milgrom, R, Dubrovsky, M, Cohen, S, Borg, A, Jernstroem, H, Lindblom, A, Rantala, J, Stenmark-Askmalm, M, Melin, B, Nathanson, K, Domchek, S, Jakubowska, A, Lubinski, J, Huzarski, T, Osorio, A, Lasa, A, Duran, M, Tejada, M-I, Godino, J, Benitez, J, Hamann, U, Kriege, M, Hoogerbrugge, N, van der Luijt, RB, van Asperen, CJ, Devilee, P, Meijers-Heijboer, HEJ, Blok, MJ, Aalfs, CM, Hogervorst, FBL, Rookus, MA, Cook, M, Oliver, C, Frost, D, Conroy, D, Evans, DG, Lalloo, F, Pichert, G, Davidson, R, Cole, T, Cook, J, Paterson, J, Hodgson, SV, Morrison, PJ, Porteous, ME, Walker, L, Kennedy, MJ, Dorkins, H, Peock, S, Godwin, AK, Stoppa-Lyonnet, D, de Pauw, A, Mazoyer, S, Bonadona, V, Lasset, C, Dreyfus, H, Leroux, D, Hardouin, A, Berthet, P, Faivre, L, Loustalot, C, Noguchi, T, Sobol, H, Rouleau, E, Nogues, C, Frenay, M, Venat-Bouvet, L, Hopper, JL, Daly, MB, Terry, MB, John, EM, Buys, S, Yassin, Y, Miron, A, Goldgar, DE, Singer, CF, Dressler, AC, Gschwantler-Kaulich, D, Pfeiler, G, Hansen, TVO, Jnson, L, Agnarsson, BA, Kirchhoff, T, Offit, K, Devlin, V, Dutra-Clarke, A, Piedmonte, M, Rodriguez, GC, Wakeley, K, Boggess, JF, Basil, J, Schwartz, PE, Blank, SV, Toland, AE, Montagna, M, Casella, C, Imyanitov, EN, Tihomirova, L, Blanco, I, Lazaro, C, Ramus, SJ, Sucheston, L, Karlan, BY, Gross, J, Schmutzler, R, Wappenschmidt, B, Engel, C, Meindl, A, Lochmann, M, Arnold, N, Heidemann, S, Varon-Mateeva, R, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Preisler-Adams, S, Kast, K, Schoenbuchner, I, Caldes, T, De La Hoya, M, Aittomaeki, K, Nevanlinna, H, Simard, J, Spurdle, AB, Holland, H, Chen, X, Platte, R, Chenevix-Trench, G & Easton, DF 2010, 'Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction', Cancer Research, vol. 70, no. 23, pp. 9742-9754. https://doi.org/10.1158/0008-5472.CAN-10-1907

TY - JOUR

T1 - Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

AU - Antoniou, Antonis C.

AU - Beesley, Jonathan

AU - McGuffog, Lesley

AU - Sinilnikova, Olga M.

AU - Healey, Sue

AU - Neuhausen, Susan L.

AU - Ding, Yuan Chun

AU - Rebbeck, Timothy R.

AU - Weitzel, Jeffrey N.

AU - Lynch, Henry T.

AU - Isaacs, Claudine

AU - Ganz, Patricia A.

AU - Tomlinson, Gail E.

AU - Olopade, Olufunmilayo I.

AU - Couch, Fergus J.

AU - Wang, Xianshu

AU - Lindor, Noralane M.

AU - Pankratz, Vernon S.

AU - Radice, Paolo

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Zaffaroni, Daniela

AU - Barile, Monica

AU - Viel, Alessandra

AU - Allavena, Anna

AU - Dall'Olio, Valentina

AU - Peterlongo, Paolo

AU - Szabo, Csilla I.

AU - Zikan, Michal

AU - Claes, Kathleen

AU - Poppe, Bruce

AU - Foretova, Lenka

AU - Mai, Phuong L.

AU - Greene, Mark H.

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Glendon, Gord

AU - Ozcelik, Hilmi

AU - Andrulis, Irene L.

AU - Thomassen, Mads

AU - Gerdes, Anne-Marie

AU - Sunde, Lone

AU - Cruger, Dorthe

AU - Jensen, Uffe Birk

AU - Caligo, Maria A.

AU - Friedman, Eitan

AU - Kaufman, Bella

AU - Laitman, Yael

AU - Milgrom, Roni

AU - Dubrovsky, Maya

AU - Cohen, Shimrit

AU - Borg, Ake

AU - Jernstroem, Helena

AU - Lindblom, Annika

AU - Rantala, Johanna

AU - Stenmark-Askmalm, Marie

AU - Melin, Beatrice

AU - Nathanson, Kate

AU - Domchek, Susan

AU - Jakubowska, Ania

AU - Lubinski, Jan

AU - Huzarski, Tomasz

AU - Osorio, Ana

AU - Lasa, Adriana

AU - Duran, Mercedes

AU - Tejada, Maria-Isabel

AU - Godino, Javier

AU - Benitez, Javier

AU - Hamann, Ute

AU - Kriege, Mieke

AU - Hoogerbrugge, Nicoline

AU - van der Luijt, Rob B.

AU - van Asperen, Christi J.

AU - Devilee, Peter

AU - Meijers-Heijboer, Hanne E. J.

AU - Blok, Marinus J.

AU - Aalfs, Cora M.

AU - Hogervorst, Frans B. L.

AU - Rookus, Matti A.

AU - Cook, Margaret

AU - Oliver, Clare

AU - Frost, Debra

AU - Conroy, Don

AU - Evans, D. Gareth

AU - Lalloo, Fiona

AU - Pichert, Gabriella

AU - Davidson, Rosemarie

AU - Cole, Trevor

AU - Cook, Jackie

AU - Paterson, Joan

AU - Hodgson, Shirley V.

AU - Morrison, Patrick J.

AU - Porteous, Mary E.

AU - Walker, Lisa

AU - Kennedy, M. John

AU - Dorkins, Huw

AU - Peock, Susan

AU - Godwin, Andrew K.

AU - Stoppa-Lyonnet, Dominique

AU - de Pauw, Antoine

AU - Mazoyer, Sylvie

AU - Bonadona, Valerie

AU - Lasset, Christine

AU - Dreyfus, Helene

AU - Leroux, Dominique

AU - Hardouin, Agnes

AU - Berthet, Pascaline

AU - Faivre, Laurence

AU - Loustalot, Catherine

AU - Noguchi, Tetsuro

AU - Sobol, Hagay

AU - Rouleau, Etienne

AU - Nogues, Catherine

AU - Frenay, Marc

AU - Venat-Bouvet, Laurence

AU - Hopper, John L.

AU - Daly, Mary B.

AU - Terry, Mary Beth

AU - John, Esther M.

AU - Buys, Saundra

AU - Yassin, Yosuf

AU - Miron, Alexander

AU - Goldgar, David E.

AU - Singer, Christian F.

AU - Dressler, Anne Catharina

AU - Gschwantler-Kaulich, Daphne

AU - Pfeiler, Georg

AU - Hansen, Thomas V. O.

AU - Jnson, Lars

AU - Agnarsson, Bjarni A.

AU - Kirchhoff, Tomas

AU - Offit, Kenneth

AU - Devlin, Vincent

AU - Dutra-Clarke, Ana

AU - Piedmonte, Marion

AU - Rodriguez, Gustavo C.

AU - Wakeley, Katie

AU - Boggess, John F.

AU - Basil, Jack

AU - Schwartz, Peter E.

AU - Blank, Stephanie V.

AU - Toland, Amanda Ewart

AU - Montagna, Marco

AU - Casella, Cinzia

AU - Imyanitov, Evgeny N.

AU - Tihomirova, Laima

AU - Blanco, Ignacio

AU - Lazaro, Conxi

AU - Ramus, Susan J.

AU - Sucheston, Lara

AU - Karlan, Beth Y.

AU - Gross, Jenny

AU - Schmutzler, Rita

AU - Wappenschmidt, Barbara

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Lochmann, Magdalena

AU - Arnold, Norbert

AU - Heidemann, Simone

AU - Varon-Mateeva, Raymonda

AU - Niederacher, Dieter

AU - Sutter, Christian

AU - Deissler, Helmut

AU - Gadzicki, Dorothea

AU - Preisler-Adams, Sabine

AU - Kast, Karin

AU - Schoenbuchner, Ines

AU - Caldes, Trinidad

AU - De La Hoya, Miguel

AU - Aittomaeki, Kristiina

AU - Nevanlinna, Heli

AU - Simard, Jacques

AU - Spurdle, Amanda B.

AU - Holland, Helene

AU - Chen, Xiaoqing

AU - Platte, Radka

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

PY - 2010/12/1

Y1 - 2010/12/1

N2 - The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 ? 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

AB - The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 ? 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

U2 - 10.1158/0008-5472.CAN-10-1907

DO - 10.1158/0008-5472.CAN-10-1907

M3 - Article

SN - 0008-5472

VL - 70

SP - 9742

EP - 9754

JO - Cancer Research

JF - Cancer Research

IS - 23

ER -

Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Abstract

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