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; ABCTB Investigators; Marcia Adams; Julian Adlard; Simona Agata; Shahana Ahmed; Habibul Ahsan; Kristiina Aittomäki; Fares Al-Ejeh; 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 E M Ausems; Jacopo Azzollini; François Bacot; Judith Balmaña; Stig E Bojesen; Anne-Marie Gerdes; Anne-Vibeke Lænkholm; Børge G Nordestgaard; Marjanka K Schmidt; Antonis C Antoniou; Jacques Simard

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, ABCTB Investigators, Marcia Adams, Julian AdlardSimona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Aittomäki, Fares Al-Ejeh, 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 E M Ausems, Jacopo Azzollini, François Bacot, Judith Balmaña, Stig E Bojesen, Anne-Marie Gerdes, Anne-Vibeke Lænkholm, Børge G Nordestgaard, Marjanka K Schmidt, Antonis C Antoniou, Jacques Simard

Department of Clinical Medicine

118 Citations (Scopus)

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
Journal	Nature Genetics
Volume	49
Issue number	12
Pages (from-to)	1767-1778
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3785
Publication status	Published - 1 Dec 2017

Keywords

BRCA1 Protein/genetics
Breast Neoplasms/ethnology
European Continental Ancestry Group/genetics
Female
Genetic Predisposition to Disease/ethnology
Genome-Wide Association Study/methods
Heterozygote
Humans
Mutation
Polymorphism, Single Nucleotide
Receptors, Estrogen/metabolism
Risk Factors

UN SDGs

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

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10.1038/ng.3785

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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., ABCTB Investigators, Adams, M., ... Simard, J. (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

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, ABCTB Investigators, Adams, M, Adlard, J, Agata, S, Ahmed, S, Ahsan, H, Aittomäki, K, Al-Ejeh, F, Allen, J, Ambrosone, CB, Amos, CI, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Auber, B, Auer, PL, Ausems, MGEM, Azzollini, J, Bacot, F, Balmaña, J, Bojesen, SE , Gerdes, A-M , Lænkholm, A-V , Nordestgaard, BG, Schmidt, MK, Antoniou, AC & Simard, J 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

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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.",

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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 {ABCTB Investigators} and Marcia Adams and Julian Adlard and Simona Agata and Shahana Ahmed and Habibul Ahsan and Kristiina Aittom{\"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 E M} and Jacopo Azzollini and Fran{\c c}ois Bacot and Judith Balma{\~n}a and Bojesen, {Stig E} and Anne-Marie Gerdes and Anne-Vibeke L{\ae}nkholm and Nordestgaard, {B{\o}rge G} and Schmidt, {Marjanka K} and Antoniou, {Antonis C} and Jacques Simard",

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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 - ABCTB Investigators

AU - Adams, Marcia

AU - Adlard, Julian

AU - Agata, Simona

AU - Ahmed, Shahana

AU - Ahsan, Habibul

AU - Aittomäki, Kristiina

AU - Al-Ejeh, Fares

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 E M

AU - Azzollini, Jacopo

AU - Bacot, François

AU - Balmaña, Judith

AU - Bojesen, Stig E

AU - Gerdes, Anne-Marie

AU - Lænkholm, Anne-Vibeke

AU - Nordestgaard, Børge G

AU - Schmidt, Marjanka K

AU - Antoniou, Antonis C

AU - Simard, Jacques

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.

KW - BRCA1 Protein/genetics

KW - Breast Neoplasms/ethnology

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genetic Predisposition to Disease/ethnology

KW - Genome-Wide Association Study/methods

KW - Heterozygote

KW - Humans

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Receptors, Estrogen/metabolism

KW - Risk Factors

U2 - 10.1038/ng.3785

DO - 10.1038/ng.3785

M3 - Journal article

C2 - 29058716

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

Keywords

UN SDGs

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