Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Karoline B. Kuchenbaecker; Susan L. Neuhausen; Mark Robson; Daniel Barrowdale; Lesley McGuffog; Anna Marie Mulligan; Irene L. Andrulis; Amanda B. Spurdle; Marjanka K. Schmidt; Rita K. Schmutzler; Christoph Engel; Barbara Wappenschmidt; Heli Nevanlinna; Mads Thomassen; Melissa Southey; Paolo Radice; Susan J. Ramus; Susan M. Domchek; Katherine L. Nathanson; Andrew Lee; Sue Healey; Robert L. Nussbaum; Timothy R. Rebbeck; Banu K. Arun; Paul James; Beth Y. Karlan; Jenny Lester; Ilana Cass; Mary Beth Terry; Mary B. Daly; David E. Goldgar; Saundra S. Buys; Ramunas Janavicius; Laima Tihomirova; Nadine Tung; Cecilia M. Dorfling; Elizabeth J. van Rensburg; Linda Steele; Thomas v O Hansen; Bent Ejlertsen; Anne Marie Gerdes; Finn C. Nielsen; Joe Dennis; Julie Cunningham; Steven Hart; Susan Slager; Ana Osorio; Javier Benitez; Mercedes Duran; Jeffrey N. Weitzel; Isaac Tafur; Mary Hander; Paolo Peterlongo; Siranoush Manoukian; Bernard Peissel; Gaia Roversi; Giulietta Scuvera; Bernardo Bonanni; Paolo Mariani; Sara Volorio; Riccardo Dolcetti; Liliana Varesco; Laura Papi; Maria Grazia Tibiletti; Giuseppe Giannini; Florentia Fostira; Irene Konstantopoulou; Judy Garber; Ute Hamann; Alan Donaldson; Carole Brewer; Claire Foo; D. Gareth Evans; Debra Frost; Diana Eccles; Fiona Douglas; Angela Brady; Jackie Cook; Marc Tischkowitz; Julian Adlard; Julian Barwell; Kai ren Ong; Lisa Walker; Louise Izatt; Lucy E. Side; M. John Kennedy; Mark T. Rogers; Mary E. Porteous; Patrick J. Morrison; Radka Platte; Ros Eeles; Rosemarie Davidson; Shirley Hodgson; Steve Ellis; Andrew K. Godwin; Kerstin Rhiem; Alfons Meindl; Nina Ditsch; Norbert Arnold; Hansjoerg Plendl; Dieter Niederacher; Christian Sutter; Doris Steinemann; Nadja Bogdanova-Markov; Karin Kast; Raymonda Varon-Mateeva; Shan Wang-Gohrke; Andrea Gehrig; Birgid Markiefka; Bruno Buecher; Cédrick Lefol; Dominique Stoppa-Lyonnet; Etienne Rouleau; Fabienne Prieur; Francesca Damiola; Laure Barjhoux; Laurence Faivre; Michel Longy; Nicolas Sevenet; Olga M. Sinilnikova; Sylvie Mazoyer; Valérie Bonadona; Virginie Caux-Moncoutier; Claudine Isaacs; Tom Van Maerken; Kathleen Claes; Marion Piedmonte; Lesley Andrews; John Hays; Gustavo C. Rodriguez; Trinidad Caldes; Miguel de la Hoya; Sofia Khan; Frans B.L. Hogervorst; Cora M. Aalfs; J. L. de Lange; Hanne E.J. Meijers-Heijboer; Annemarie H. van der Hout; Juul T. Wijnen; K. E.P. van Roozendaal; Arjen R. Mensenkamp; Ans M.W. van den Ouweland; Carolien H.M. van Deurzen; Rob B. van der Luijt; Edith Olah; Orland Diez; Conxi Lazaro; Ignacio Blanco; Alex Teulé; Mireia Menendez; Anna Jakubowska; Jan Lubinski; Cezary Cybulski; Jacek Gronwald; Katarzyna Jaworska-Bieniek; Katarzyna Durda; Adalgeir Arason; Christine Maugard; Penny Soucy; Marco Montagna; Simona Agata; Manuel R. Teixeira; Curtis Olswold; Noralane Lindor; Vernon S. Pankratz; Emily Hallberg; Xianshu Wang; Csilla I. Szabo; Joseph Vijai; Lauren Jacobs; Marina Corines; Anne Lincoln; Andreas Berger; Anneliese Fink-Retter; Christian F. Singer; Christine Rappaport; Daphne Gschwantler Kaulich; Georg Pfeiler; Muy Kheng Tea; Catherine M. Phelan; Phuong L. Mai; Mark H. Greene; Gad Rennert; Evgeny N. Imyanitov; Gord Glendon; Amanda Ewart Toland; Anders Bojesen; Inge Sokilde Pedersen; Uffe Birk Jensen; Maria A. Caligo; Eitan Friedman; Raanan Berger; Yael Laitman; Johanna Rantala; Brita Arver; Niklas Loman; Ake Borg; Hans Ehrencrona; Olufunmilayo I. Olopade; Jacques Simard; Douglas F. Easton; Georgia Chenevix-Trench; Kenneth Offit; Fergus J. Couch; Antonis C. Antoniou; CIMBA; Study EMBRACE Study; Cancer Family Breast Cancer Family; Study Collaborators GEMO Study Collaborators; HEBON; Investigators KConFab Investigators

doi:10.1186/s13058-014-0492-9

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Karoline B. Kuchenbaecker, Susan L. Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L. Andrulis, Amanda B. Spurdle, Marjanka K. Schmidt, Rita K. Schmutzler, Christoph Engel, Barbara Wappenschmidt, Heli Nevanlinna, Mads Thomassen, Melissa Southey, Paolo Radice, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Andrew LeeSue Healey, Robert L. Nussbaum, Timothy R. Rebbeck, Banu K. Arun, Paul James, Beth Y. Karlan, Jenny Lester, Ilana Cass, Mary Beth Terry, Mary B. Daly, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Thomas v O Hansen, Bent Ejlertsen, Anne Marie Gerdes, Finn C. Nielsen, Joe Dennis, Julie Cunningham, Steven Hart, Susan Slager, Ana Osorio, Javier Benitez, Mercedes Duran, Jeffrey N. Weitzel, Isaac Tafur, Mary Hander, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Gaia Roversi, Giulietta Scuvera, Bernardo Bonanni, Paolo Mariani, Sara Volorio, Riccardo Dolcetti, Liliana Varesco, Laura Papi, Maria Grazia Tibiletti, Giuseppe Giannini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, Fiona Douglas, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Kai ren Ong, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Andrew K. Godwin, Kerstin Rhiem, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Doris Steinemann, Nadja Bogdanova-Markov, Karin Kast, Raymonda Varon-Mateeva, Shan Wang-Gohrke, Andrea Gehrig, Birgid Markiefka, Bruno Buecher, Cédrick Lefol, Dominique Stoppa-Lyonnet, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Laure Barjhoux, Laurence Faivre, Michel Longy, Nicolas Sevenet, Olga M. Sinilnikova, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Claudine Isaacs, Tom Van Maerken, Kathleen Claes, Marion Piedmonte, Lesley Andrews, John Hays, Gustavo C. Rodriguez, Trinidad Caldes, Miguel de la Hoya, Sofia Khan, Frans B.L. Hogervorst, Cora M. Aalfs, J. L. de Lange, Hanne E.J. Meijers-Heijboer, Annemarie H. van der Hout, Juul T. Wijnen, K. E.P. van Roozendaal, Arjen R. Mensenkamp, Ans M.W. van den Ouweland, Carolien H.M. van Deurzen, Rob B. van der Luijt, Edith Olah, Orland Diez, Conxi Lazaro, Ignacio Blanco, Alex Teulé, Mireia Menendez, Anna Jakubowska, Jan Lubinski, Cezary Cybulski, Jacek Gronwald, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Adalgeir Arason, Christine Maugard, Penny Soucy, Marco Montagna, Simona Agata, Manuel R. Teixeira, Curtis Olswold, Noralane Lindor, Vernon S. Pankratz, Emily Hallberg, Xianshu Wang, Csilla I. Szabo, Joseph Vijai, Lauren Jacobs, Marina Corines, Anne Lincoln, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Gschwantler Kaulich, Georg Pfeiler, Muy Kheng Tea, Catherine M. Phelan, Phuong L. Mai, Mark H. Greene, Gad Rennert, Evgeny N. Imyanitov, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Raanan Berger, Yael Laitman, Johanna Rantala, Brita Arver, Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo I. Olopade, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Kenneth Offit, Fergus J. Couch, Antonis C. Antoniou, CIMBA, Study EMBRACE Study, Cancer Family Breast Cancer Family, Study Collaborators GEMO Study Collaborators, HEBON, Investigators KConFab Investigators

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

32 Scopus citations

Abstract

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10^-6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Original language	English (US)
Article number	3416
Journal	Breast Cancer Research
Volume	16
DOIs	https://doi.org/10.1186/s13058-014-0492-9
State	Published - Dec 31 2014

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1186/s13058-014-0492-9

Cite this

Kuchenbaecker, K. B., Neuhausen, S. L., Robson, M., Barrowdale, D., McGuffog, L., Mulligan, A. M., Andrulis, I. L., Spurdle, A. B., Schmidt, M. K., Schmutzler, R. K., Engel, C., Wappenschmidt, B., Nevanlinna, H., Thomassen, M., Southey, M., Radice, P., Ramus, S. J., Domchek, S. M., Nathanson, K. L., ... KConFab Investigators, I. (2014). Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. Breast Cancer Research, 16, Article 3416. https://doi.org/10.1186/s13058-014-0492-9

Kuchenbaecker, KB, Neuhausen, SL, Robson, M, Barrowdale, D, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, SJ, Domchek, SM, Nathanson, KL, Lee, A, Healey, S, Nussbaum, RL, Rebbeck, TR, Arun, BK, James, P, Karlan, BY, Lester, J, Cass, I, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Steele, L, v O Hansen, T, Ejlertsen, B, Gerdes, AM, Nielsen, FC, Dennis, J, Cunningham, J , Hart, S , Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, JN, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, MG, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, KR, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, AK, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova-Markov, N, Kast, K, Varon-Mateeva, R, Wang-Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa-Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, OM, Mazoyer, S, Bonadona, V, Caux-Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, GC, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, FBL, Aalfs, CM, de Lange, JL, Meijers-Heijboer, HEJ, van der Hout, AH, Wijnen, JT, van Roozendaal, KEP, Mensenkamp, AR, van den Ouweland, AMW, van Deurzen, CHM, van der Luijt, RB, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska-Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, MR, Olswold, C, Lindor, N, Pankratz, VS, Hallberg, E, Wang, X, Szabo, CI, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, MK, Phelan, CM, Mai, PL, Greene, MH, Rennert, G, Imyanitov, EN, Glendon, G, Toland, AE, Bojesen, A, Pedersen, IS, Jensen, UB, Caligo, MA, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, OI, Simard, J, Easton, DF, Chenevix-Trench, G, Offit, K, Couch, FJ, Antoniou, AC, CIMBA, EMBRACE Study, S, Breast Cancer Family, CF, GEMO Study Collaborators, SC, HEBON & KConFab Investigators, I 2014, 'Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers', Breast Cancer Research, vol. 16, 3416. https://doi.org/10.1186/s13058-014-0492-9

@article{1da6ab7962ca435792bc12555c6bd5f1,

title = "Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers",

abstract = "Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10-6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.",

author = "Kuchenbaecker, {Karoline B.} and Neuhausen, {Susan L.} and Mark Robson and Daniel Barrowdale and Lesley McGuffog and Mulligan, {Anna Marie} and Andrulis, {Irene L.} and Spurdle, {Amanda B.} and Schmidt, {Marjanka K.} and Schmutzler, {Rita K.} and Christoph Engel and Barbara Wappenschmidt and Heli Nevanlinna and Mads Thomassen and Melissa Southey and Paolo Radice and Ramus, {Susan J.} and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Andrew Lee and Sue Healey and Nussbaum, {Robert L.} and Rebbeck, {Timothy R.} and Arun, {Banu K.} and Paul James and Karlan, {Beth Y.} and Jenny Lester and Ilana Cass and Terry, {Mary Beth} and Daly, {Mary B.} and Goldgar, {David E.} and Buys, {Saundra S.} and Ramunas Janavicius and Laima Tihomirova and Nadine Tung and Dorfling, {Cecilia M.} and {van Rensburg}, {Elizabeth J.} and Linda Steele and {v O Hansen}, Thomas and Bent Ejlertsen and Gerdes, {Anne Marie} and Nielsen, {Finn C.} and Joe Dennis and Julie Cunningham and Steven Hart and Susan Slager and Ana Osorio and Javier Benitez and Mercedes Duran and Weitzel, {Jeffrey N.} and Isaac Tafur and Mary Hander and Paolo Peterlongo and Siranoush Manoukian and Bernard Peissel and Gaia Roversi and Giulietta Scuvera and Bernardo Bonanni and Paolo Mariani and Sara Volorio and Riccardo Dolcetti and Liliana Varesco and Laura Papi and Tibiletti, {Maria Grazia} and Giuseppe Giannini and Florentia Fostira and Irene Konstantopoulou and Judy Garber and Ute Hamann and Alan Donaldson and Carole Brewer and Claire Foo and Evans, {D. Gareth} and Debra Frost and Diana Eccles and Fiona Douglas and Angela Brady and Jackie Cook and Marc Tischkowitz and Julian Adlard and Julian Barwell and Ong, {Kai ren} and Lisa Walker and Louise Izatt and Side, {Lucy E.} and Kennedy, {M. John} and Rogers, {Mark T.} and Porteous, {Mary E.} and Morrison, {Patrick J.} and Radka Platte and Ros Eeles and Rosemarie Davidson and Shirley Hodgson and Steve Ellis and Godwin, {Andrew K.} and Kerstin Rhiem and Alfons Meindl and Nina Ditsch and Norbert Arnold and Hansjoerg Plendl and Dieter Niederacher and Christian Sutter and Doris Steinemann and Nadja Bogdanova-Markov and Karin Kast and Raymonda Varon-Mateeva and Shan Wang-Gohrke and Andrea Gehrig and Birgid Markiefka and Bruno Buecher and C{\'e}drick Lefol and Dominique Stoppa-Lyonnet and Etienne Rouleau and Fabienne Prieur and Francesca Damiola and Laure Barjhoux and Laurence Faivre and Michel Longy and Nicolas Sevenet and Sinilnikova, {Olga M.} and Sylvie Mazoyer and Val{\'e}rie Bonadona and Virginie Caux-Moncoutier and Claudine Isaacs and {Van Maerken}, Tom and Kathleen Claes and Marion Piedmonte and Lesley Andrews and John Hays and Rodriguez, {Gustavo C.} and Trinidad Caldes and {de la Hoya}, Miguel and Sofia Khan and Hogervorst, {Frans B.L.} and Aalfs, {Cora M.} and {de Lange}, {J. L.} and Meijers-Heijboer, {Hanne E.J.} and {van der Hout}, {Annemarie H.} and Wijnen, {Juul T.} and {van Roozendaal}, {K. E.P.} and Mensenkamp, {Arjen R.} and {van den Ouweland}, {Ans M.W.} and {van Deurzen}, {Carolien H.M.} and {van der Luijt}, {Rob B.} and Edith Olah and Orland Diez and Conxi Lazaro and Ignacio Blanco and Alex Teul{\'e} and Mireia Menendez and Anna Jakubowska and Jan Lubinski and Cezary Cybulski and Jacek Gronwald and Katarzyna Jaworska-Bieniek and Katarzyna Durda and Adalgeir Arason and Christine Maugard and Penny Soucy and Marco Montagna and Simona Agata and Teixeira, {Manuel R.} and Curtis Olswold and Noralane Lindor and Pankratz, {Vernon S.} and Emily Hallberg and Xianshu Wang and Szabo, {Csilla I.} and Joseph Vijai and Lauren Jacobs and Marina Corines and Anne Lincoln and Andreas Berger and Anneliese Fink-Retter and Singer, {Christian F.} and Christine Rappaport and Kaulich, {Daphne Gschwantler} and Georg Pfeiler and Tea, {Muy Kheng} and Phelan, {Catherine M.} and Mai, {Phuong L.} and Greene, {Mark H.} and Gad Rennert and Imyanitov, {Evgeny N.} and Gord Glendon and Toland, {Amanda Ewart} and Anders Bojesen and Pedersen, {Inge Sokilde} and Jensen, {Uffe Birk} and Caligo, {Maria A.} and Eitan Friedman and Raanan Berger and Yael Laitman and Johanna Rantala and Brita Arver and Niklas Loman and Ake Borg and Hans Ehrencrona and Olopade, {Olufunmilayo I.} and Jacques Simard and Easton, {Douglas F.} and Georgia Chenevix-Trench and Kenneth Offit and Couch, {Fergus J.} and Antoniou, {Antonis C.} and CIMBA and {EMBRACE Study}, Study and {Breast Cancer Family}, {Cancer Family} and {GEMO Study Collaborators}, {Study Collaborators} and HEBON and {KConFab Investigators}, Investigators",

note = "Publisher Copyright: {\textcopyright} 2014 Kuchenbaecker et al.",

year = "2014",

month = dec,

day = "31",

doi = "10.1186/s13058-014-0492-9",

language = "English (US)",

volume = "16",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central",

}

TY - JOUR

T1 - Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

AU - Kuchenbaecker, Karoline B.

AU - Neuhausen, Susan L.

AU - Robson, Mark

AU - Barrowdale, Daniel

AU - McGuffog, Lesley

AU - Mulligan, Anna Marie

AU - Andrulis, Irene L.

AU - Spurdle, Amanda B.

AU - Schmidt, Marjanka K.

AU - Schmutzler, Rita K.

AU - Engel, Christoph

AU - Wappenschmidt, Barbara

AU - Nevanlinna, Heli

AU - Thomassen, Mads

AU - Southey, Melissa

AU - Radice, Paolo

AU - Ramus, Susan J.

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Lee, Andrew

AU - Healey, Sue

AU - Nussbaum, Robert L.

AU - Rebbeck, Timothy R.

AU - Arun, Banu K.

AU - James, Paul

AU - Karlan, Beth Y.

AU - Lester, Jenny

AU - Cass, Ilana

AU - Terry, Mary Beth

AU - Daly, Mary B.

AU - Goldgar, David E.

AU - Buys, Saundra S.

AU - Janavicius, Ramunas

AU - Tihomirova, Laima

AU - Tung, Nadine

AU - Dorfling, Cecilia M.

AU - van Rensburg, Elizabeth J.

AU - Steele, Linda

AU - v O Hansen, Thomas

AU - Ejlertsen, Bent

AU - Gerdes, Anne Marie

AU - Nielsen, Finn C.

AU - Dennis, Joe

AU - Cunningham, Julie

AU - Hart, Steven

AU - Slager, Susan

AU - Osorio, Ana

AU - Benitez, Javier

AU - Duran, Mercedes

AU - Weitzel, Jeffrey N.

AU - Tafur, Isaac

AU - Hander, Mary

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Roversi, Gaia

AU - Scuvera, Giulietta

AU - Bonanni, Bernardo

AU - Mariani, Paolo

AU - Volorio, Sara

AU - Dolcetti, Riccardo

AU - Varesco, Liliana

AU - Papi, Laura

AU - Tibiletti, Maria Grazia

AU - Giannini, Giuseppe

AU - Fostira, Florentia

AU - Konstantopoulou, Irene

AU - Garber, Judy

AU - Hamann, Ute

AU - Donaldson, Alan

AU - Brewer, Carole

AU - Foo, Claire

AU - Evans, D. Gareth

AU - Frost, Debra

AU - Eccles, Diana

AU - Douglas, Fiona

AU - Brady, Angela

AU - Cook, Jackie

AU - Tischkowitz, Marc

AU - Adlard, Julian

AU - Barwell, Julian

AU - Ong, Kai ren

AU - Walker, Lisa

AU - Izatt, Louise

AU - Side, Lucy E.

AU - Kennedy, M. John

AU - Rogers, Mark T.

AU - Porteous, Mary E.

AU - Morrison, Patrick J.

AU - Platte, Radka

AU - Eeles, Ros

AU - Davidson, Rosemarie

AU - Hodgson, Shirley

AU - Ellis, Steve

AU - Godwin, Andrew K.

AU - Rhiem, Kerstin

AU - Meindl, Alfons

AU - Ditsch, Nina

AU - Arnold, Norbert

AU - Plendl, Hansjoerg

AU - Niederacher, Dieter

AU - Sutter, Christian

AU - Steinemann, Doris

AU - Bogdanova-Markov, Nadja

AU - Kast, Karin

AU - Varon-Mateeva, Raymonda

AU - Wang-Gohrke, Shan

AU - Gehrig, Andrea

AU - Markiefka, Birgid

AU - Buecher, Bruno

AU - Lefol, Cédrick

AU - Stoppa-Lyonnet, Dominique

AU - Rouleau, Etienne

AU - Prieur, Fabienne

AU - Damiola, Francesca

AU - Barjhoux, Laure

AU - Faivre, Laurence

AU - Longy, Michel

AU - Sevenet, Nicolas

AU - Sinilnikova, Olga M.

AU - Mazoyer, Sylvie

AU - Bonadona, Valérie

AU - Caux-Moncoutier, Virginie

AU - Isaacs, Claudine

AU - Van Maerken, Tom

AU - Claes, Kathleen

AU - Piedmonte, Marion

AU - Andrews, Lesley

AU - Hays, John

AU - Rodriguez, Gustavo C.

AU - Caldes, Trinidad

AU - de la Hoya, Miguel

AU - Khan, Sofia

AU - Hogervorst, Frans B.L.

AU - Aalfs, Cora M.

AU - de Lange, J. L.

AU - Meijers-Heijboer, Hanne E.J.

AU - van der Hout, Annemarie H.

AU - Wijnen, Juul T.

AU - van Roozendaal, K. E.P.

AU - Mensenkamp, Arjen R.

AU - van den Ouweland, Ans M.W.

AU - van Deurzen, Carolien H.M.

AU - van der Luijt, Rob B.

AU - Olah, Edith

AU - Diez, Orland

AU - Lazaro, Conxi

AU - Blanco, Ignacio

AU - Teulé, Alex

AU - Menendez, Mireia

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Cybulski, Cezary

AU - Gronwald, Jacek

AU - Jaworska-Bieniek, Katarzyna

AU - Durda, Katarzyna

AU - Arason, Adalgeir

AU - Maugard, Christine

AU - Soucy, Penny

AU - Montagna, Marco

AU - Agata, Simona

AU - Teixeira, Manuel R.

AU - Olswold, Curtis

AU - Lindor, Noralane

AU - Pankratz, Vernon S.

AU - Hallberg, Emily

AU - Wang, Xianshu

AU - Szabo, Csilla I.

AU - Vijai, Joseph

AU - Jacobs, Lauren

AU - Corines, Marina

AU - Lincoln, Anne

AU - Berger, Andreas

AU - Fink-Retter, Anneliese

AU - Singer, Christian F.

AU - Rappaport, Christine

AU - Kaulich, Daphne Gschwantler

AU - Pfeiler, Georg

AU - Tea, Muy Kheng

AU - Phelan, Catherine M.

AU - Mai, Phuong L.

AU - Greene, Mark H.

AU - Rennert, Gad

AU - Imyanitov, Evgeny N.

AU - Glendon, Gord

AU - Toland, Amanda Ewart

AU - Bojesen, Anders

AU - Pedersen, Inge Sokilde

AU - Jensen, Uffe Birk

AU - Caligo, Maria A.

AU - Friedman, Eitan

AU - Berger, Raanan

AU - Laitman, Yael

AU - Rantala, Johanna

AU - Arver, Brita

AU - Loman, Niklas

AU - Borg, Ake

AU - Ehrencrona, Hans

AU - Olopade, Olufunmilayo I.

AU - Simard, Jacques

AU - Easton, Douglas F.

AU - Chenevix-Trench, Georgia

AU - Offit, Kenneth

AU - Couch, Fergus J.

AU - Antoniou, Antonis C.

AU - CIMBA,

AU - EMBRACE Study, Study

AU - Breast Cancer Family, Cancer Family

AU - GEMO Study Collaborators, Study Collaborators

AU - HEBON,

AU - KConFab Investigators, Investigators

PY - 2014/12/31

Y1 - 2014/12/31

N2 - Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10-6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

AB - Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10-6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

UR - http://www.scopus.com/inward/record.url?scp=84928558663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928558663&partnerID=8YFLogxK

U2 - 10.1186/s13058-014-0492-9

DO - 10.1186/s13058-014-0492-9

M3 - Article

C2 - 25919761

AN - SCOPUS:84928558663

SN - 1465-5411

VL - 16

JO - Breast Cancer Research

JF - Breast Cancer Research

M1 - 3416

ER -

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

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