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 Lindstrom; Shirley Hui; Audrey Lemacon; Penny Soucy; Joe Dennis; Xia Jiang; Asha Rostamianfar; Hilary Finucane; Manjeet K. Bolla; Lesley McGuffog; Qin Wang; Cora M. Aalfs; Marcia Adams; Julian Adlard; Simona Agata; Shahana Ahmed; Habibul Ahsan; Kristiina Aittomaki; 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; Francois Bacot; Judith Balmana; Monica Barile; Laure Barjhoux; Rosa B. Barkardottir; Myrto Barrdahl; Daniel Barnes; Daniel Barrowdale; Caroline Baynes; Matthias W. Beckmann; Javier Benitez; Marina Bermisheva; Marinus J. Blok; ABCTB Investigators; EMBRACE; GEMO Study Collaborators; HEBON; kConFab AOCS Investigators; 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 Lindstrom, Shirley Hui, Audrey Lemacon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K. Bolla, Lesley McGuffog, Qin Wang, Cora M. Aalfs, Marcia Adams, Julian Adlard, Simona AgataShahana Ahmed, Habibul Ahsan, Kristiina Aittomaki, 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, Francois Bacot, Judith Balmana, Monica Barile, Laure Barjhoux, Rosa B. Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W. Beckmann, Javier Benitez, Marina Bermisheva, Marinus J. Blok, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab AOCS Investigators, NBSC Collaborators

^*Corresponding author for this work

Research output: Contribution to journal › Comment/Letter to the editor › Academic › peer-review

179 Citations (Web of Science)

Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease(1). 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 x 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	12
Journal	Nature Genetics
Volume	49
Issue number	12
DOIs	https://doi.org/10.1038/ng.3785
Publication status	Published - Dec 2017

Keywords

GENOME-WIDE ASSOCIATION
BRCA2 MUTATION CARRIERS
SUSCEPTIBILITY LOCI
CONFER SUSCEPTIBILITY
FUNCTIONAL VARIANTS
OVARIAN CANCERS
COMMON VARIANTS
CONSORTIUM
EXPRESSION
DISEASE

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Milne, R. L., Kuchenbaecker, K. B., Michailidou, K., Beesley, J., Kar, S., Lindstrom, S., Hui, S., Lemacon, A., Soucy, P., Dennis, J., Jiang, X., Rostamianfar, A., Finucane, H., Bolla, M. K., McGuffog, L., Wang, Q., Aalfs, C. M., Adams, M., Adlard, J., ... 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{4f8a0fff94df4caf9954a8e012ae5144,

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 disease(1). 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 x 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.",

keywords = "GENOME-WIDE ASSOCIATION, BRCA2 MUTATION CARRIERS, SUSCEPTIBILITY LOCI, CONFER SUSCEPTIBILITY, FUNCTIONAL VARIANTS, OVARIAN CANCERS, COMMON VARIANTS, CONSORTIUM, EXPRESSION, DISEASE",

author = "Milne, {Roger L.} and Kuchenbaecker, {Karoline B.} and Kyriaki Michailidou and Jonathan Beesley and Siddhartha Kar and Sara Lindstrom and Shirley Hui and Audrey Lemacon 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 Marcia Adams and Julian Adlard and Simona Agata and Shahana Ahmed and Habibul Ahsan and Kristiina Aittomaki 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 Francois Bacot and Judith Balmana 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 Marina Bermisheva and Blok, {Marinus J.} and {ABCTB Investigators} and EMBRACE and {GEMO Study Collaborators} and HEBON and {kConFab AOCS Investigators} and {NBSC Collaborators}",

year = "2017",

month = dec,

doi = "10.1038/ng.3785",

language = "English",

volume = "49",

pages = "1767--1778",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

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Milne, RL, Kuchenbaecker, KB, Michailidou, K, Beesley, J, Kar, S, Lindstrom, S, Hui, S, Lemacon, A, Soucy, P, Dennis, J, Jiang, X, Rostamianfar, A, Finucane, H, Bolla, MK, McGuffog, L, Wang, Q, Aalfs, CM, Adams, M, Adlard, J, Agata, S, Ahmed, S, Ahsan, H, Aittomaki, 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, Balmana, J, Barile, M, Barjhoux, L, Barkardottir, RB, Barrdahl, M, Barnes, D, Barrowdale, D, Baynes, C, Beckmann, MW, Benitez, J, Bermisheva, M, Blok, MJ, ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab AOCS Investigators & 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 - Lindstrom, Sara

AU - Hui, Shirley

AU - Lemacon, 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 - Adams, Marcia

AU - Adlard, Julian

AU - Agata, Simona

AU - Ahmed, Shahana

AU - Ahsan, Habibul

AU - Aittomaki, 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, Francois

AU - Balmana, Judith

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 - Bermisheva, Marina

AU - Blok, Marinus J.

AU - ABCTB Investigators

AU - EMBRACE

AU - GEMO Study Collaborators

AU - HEBON

AU - kConFab AOCS Investigators

AU - NBSC Collaborators

PY - 2017/12

Y1 - 2017/12

N2 - Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease(1). 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 x 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 disease(1). 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 x 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 - GENOME-WIDE ASSOCIATION

KW - BRCA2 MUTATION CARRIERS

KW - SUSCEPTIBILITY LOCI

KW - CONFER SUSCEPTIBILITY

KW - FUNCTIONAL VARIANTS

KW - OVARIAN CANCERS

KW - COMMON VARIANTS

KW - CONSORTIUM

KW - EXPRESSION

KW - DISEASE

U2 - 10.1038/ng.3785

DO - 10.1038/ng.3785

M3 - Comment/Letter to the editor

C2 - 29058716

SN - 1061-4036

VL - 49

SP - 1767

EP - 1778

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -