Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Roger L. Milne; Karoline B. Kuchenbaecker; Kyriaki Michailidou; Jonathan Beesley; Siddhartha Kar; Sara Lindström; Shirley Hui; Audrey Lemaçon; Penny Soucy; Joe Dennis; Xia Jiang; Asha Rostamianfar; Hilary Finucane; Manjeet K. Bolla; Lesley McGuffog; Qin Wang; Cora M. Aalfs; Investigators Abctctb; Marcia Adams; Julian Adlard; Simona Agata; Shahana Ahmed; Habibul Ahsan; Kristiina Äki Aittom; Al Ejeh Fares; Jamie Allen; Christine B. Ambrosone; Christopher I. Amos; Irene L. Andrulis; Hoda Anton-Culver; Natalia N. Antonenkova; Volker Arndt; Norbert Arnold; Kristan J. Aronson; Bernd Auber; Paul L. Auer; Margreet G.M. Ausems; Jacopo Azzollini; Bacot François; Judith Nã Balma; Monica Barile; Laure Barjhoux; Rosa B. Barkardottir; Myrto Barrdahl; Daniel Barnes; Daniel Barrowdale; Caroline Baynes; Matthias W. Beckmann; Javier Benitez; Nick Orr; ABCTB Investigators; EMBRACE; GEMO Study Collaborators; NBSC Collaborators

doi:10.1038/ng.3785

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Roger L. Milne^*, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindström, Shirley Hui, Audrey Lemaçon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K. Bolla, Lesley McGuffog, Qin Wang, Cora M. Aalfs, Investigators Abctctb, Marcia Adams, Julian AdlardSimona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Äki Aittom, Al Ejeh Fares, Jamie Allen, Christine B. Ambrosone, Christopher I. Amos, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Bernd Auber, Paul L. Auer, Margreet G.M. Ausems, Jacopo Azzollini, Bacot François, Judith Nã Balma, Monica Barile, Laure Barjhoux, Rosa B. Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W. Beckmann, Javier Benitez, Nick Orr, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, NBSC Collaborators

^*Corresponding author for this work

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Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10^-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Original language	English
Pages (from-to)	1767-1778
Number of pages	15
Journal	Nature Genetics
Volume	49
Issue number	12
Early online date	23 Oct 2017
DOIs	https://doi.org/10.1038/ng.3785
Publication status	Published - 01 Dec 2017
Externally published	Yes

Bibliographical note

Funding Information:
We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. Genotyping for the OncoArray was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1 U19 CA 148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control–Ministry of Health and Welfare (Republic of Korea) (1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837). Genotyping for the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174]), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Ministère de l’Économie, Innovation et Exportation du Québec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Combination of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative (1 U19 CA 148065) (DRIVE, part of the GAME-ON initiative). LD score regression analysis was supported by grant CA194393. BCAC is funded by Cancer Research UK (C1287/A16563) and by the European Union via its Seventh Framework Programme (HEALTH-F2-2009-223175, COGS) and the Horizon 2020 Research and Innovation Programme (633784, B-CAST; 634935, BRIDGES). CIMBA is funded by Cancer Research UK (C12292/A20861 and C12292/A11174). For a full description of funding and acknowledgments, see the Supplementary Note.

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ten variants associated with risk of estrogen receptor negative breast cancer
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Milne, R. L., Kuchenbaecker, K. B., Michailidou, K., Beesley, J., Kar, S., Lindström, S., Hui, S., Lemaçon, A., Soucy, P., Dennis, J., Jiang, X., Rostamianfar, A., Finucane, H., Bolla, M. K., McGuffog, L., Wang, Q., Aalfs, C. M., Abctctb, I., Adams, M., ... NBSC Collaborators (2017). Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nature Genetics, 49(12), 1767-1778. https://doi.org/10.1038/ng.3785

@article{26fc3791ba6b4818818a7790df4a2748,

title = "Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer",

abstract = "Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.",

author = "Milne, {Roger L.} and Kuchenbaecker, {Karoline B.} and Kyriaki Michailidou and Jonathan Beesley and Siddhartha Kar and Sara Lindstr{\"o}m and Shirley Hui and Audrey Lema{\c c}on and Penny Soucy and Joe Dennis and Xia Jiang and Asha Rostamianfar and Hilary Finucane and Bolla, {Manjeet K.} and Lesley McGuffog and Qin Wang and Aalfs, {Cora M.} and Investigators Abctctb and Marcia Adams and Julian Adlard and Simona Agata and Shahana Ahmed and Habibul Ahsan and Aittom, {Kristiina {\"A}ki} and Fares, {Al Ejeh} and Jamie Allen and Ambrosone, {Christine B.} and Amos, {Christopher I.} and Andrulis, {Irene L.} and Hoda Anton-Culver and Antonenkova, {Natalia N.} and Volker Arndt and Norbert Arnold and Aronson, {Kristan J.} and Bernd Auber and Auer, {Paul L.} and Ausems, {Margreet G.M.} and Jacopo Azzollini and Bacot Fran{\c c}ois and Balma, {Judith N{\~a}} and Monica Barile and Laure Barjhoux and Barkardottir, {Rosa B.} and Myrto Barrdahl and Daniel Barnes and Daniel Barrowdale and Caroline Baynes and Beckmann, {Matthias W.} and Javier Benitez and Nick Orr and {ABCTB Investigators} and EMBRACE and {GEMO Study Collaborators} and {NBSC Collaborators}",

note = "Funding Information: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. Genotyping for the OncoArray was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Minist{\`e}re de l{\textquoteright}{\'E}conomie, de la Science et de l{\textquoteright}Innovation du Qu{\'e}bec through G{\'e}nome Qu{\'e}bec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1 U19 CA 148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control–Ministry of Health and Welfare (Republic of Korea) (1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837). Genotyping for the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174]), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Minist{\`e}re de l{\textquoteright}{\'E}conomie, Innovation et Exportation du Qu{\'e}bec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Combination of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative (1 U19 CA 148065) (DRIVE, part of the GAME-ON initiative). LD score regression analysis was supported by grant CA194393. BCAC is funded by Cancer Research UK (C1287/A16563) and by the European Union via its Seventh Framework Programme (HEALTH-F2-2009-223175, COGS) and the Horizon 2020 Research and Innovation Programme (633784, B-CAST; 634935, BRIDGES). CIMBA is funded by Cancer Research UK (C12292/A20861 and C12292/A11174). For a full description of funding and acknowledgments, see the Supplementary Note.",

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doi = "10.1038/ng.3785",

language = "English",

volume = "49",

pages = "1767--1778",

journal = "Nature Genetics",

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Milne, RL, Kuchenbaecker, KB, Michailidou, K, Beesley, J, Kar, S, Lindström, S, Hui, S, Lemaçon, A, Soucy, P, Dennis, J, Jiang, X, Rostamianfar, A, Finucane, H, Bolla, MK, McGuffog, L, Wang, Q, Aalfs, CM, Abctctb, I, Adams, M, Adlard, J, Agata, S, Ahmed, S, Ahsan, H, Aittom, KÄ, Fares, AE, Allen, J, Ambrosone, CB, Amos, CI, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Auber, B, Auer, PL, Ausems, MGM, Azzollini, J, François, B, Balma, JN, Barile, M, Barjhoux, L, Barkardottir, RB, Barrdahl, M, Barnes, D, Barrowdale, D, Baynes, C, Beckmann, MW, Benitez, J, Orr, N, ABCTB Investigators, EMBRACE, GEMO Study Collaborators & NBSC Collaborators 2017, 'Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer', Nature Genetics, vol. 49, no. 12, pp. 1767-1778. https://doi.org/10.1038/ng.3785

TY - JOUR

T1 - Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

AU - Milne, Roger L.

AU - Kuchenbaecker, Karoline B.

AU - Michailidou, Kyriaki

AU - Beesley, Jonathan

AU - Kar, Siddhartha

AU - Lindström, Sara

AU - Hui, Shirley

AU - Lemaçon, Audrey

AU - Soucy, Penny

AU - Dennis, Joe

AU - Jiang, Xia

AU - Rostamianfar, Asha

AU - Finucane, Hilary

AU - Bolla, Manjeet K.

AU - McGuffog, Lesley

AU - Wang, Qin

AU - Aalfs, Cora M.

AU - Abctctb, Investigators

AU - Adams, Marcia

AU - Adlard, Julian

AU - Agata, Simona

AU - Ahmed, Shahana

AU - Ahsan, Habibul

AU - Aittom, Kristiina Äki

AU - Fares, Al Ejeh

AU - Allen, Jamie

AU - Ambrosone, Christine B.

AU - Amos, Christopher I.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N.

AU - Arndt, Volker

AU - Arnold, Norbert

AU - Aronson, Kristan J.

AU - Auber, Bernd

AU - Auer, Paul L.

AU - Ausems, Margreet G.M.

AU - Azzollini, Jacopo

AU - François, Bacot

AU - Balma, Judith Nã

AU - Barile, Monica

AU - Barjhoux, Laure

AU - Barkardottir, Rosa B.

AU - Barrdahl, Myrto

AU - Barnes, Daniel

AU - Barrowdale, Daniel

AU - Baynes, Caroline

AU - Beckmann, Matthias W.

AU - Benitez, Javier

AU - Orr, Nick

AU - ABCTB Investigators

AU - EMBRACE

AU - GEMO Study Collaborators

AU - NBSC Collaborators

N1 - Funding Information: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. Genotyping for the OncoArray was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1 U19 CA 148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control–Ministry of Health and Welfare (Republic of Korea) (1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837). Genotyping for the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174]), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Ministère de l’Économie, Innovation et Exportation du Québec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Combination of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative (1 U19 CA 148065) (DRIVE, part of the GAME-ON initiative). LD score regression analysis was supported by grant CA194393. BCAC is funded by Cancer Research UK (C1287/A16563) and by the European Union via its Seventh Framework Programme (HEALTH-F2-2009-223175, COGS) and the Horizon 2020 Research and Innovation Programme (633784, B-CAST; 634935, BRIDGES). CIMBA is funded by Cancer Research UK (C12292/A20861 and C12292/A11174). For a full description of funding and acknowledgments, see the Supplementary Note.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

AB - Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

U2 - 10.1038/ng.3785

DO - 10.1038/ng.3785

M3 - Article

AN - SCOPUS:85035773185

SN - 1061-4036

VL - 49

SP - 1767

EP - 1778

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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