Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Haoyu Zhang; Thomas U. Ahearn; Julie Lecarpentier; Daniel Barnes; Jonathan Beesley; Guanghao Qi; Xia Jiang; Tracy A. O’Mara; Ni Zhao; Manjeet K. Bolla; Alison M. Dunning; Joe Dennis; Qin Wang; Zumuruda Abu Ful; Kristiina Aittomäki; Irene L. Andrulis; Hoda Anton-Culver; Volker Arndt; Kristan J. Aronson; Banu K. Arun; Paul L. Auer; Jacopo Azzollini; Daniel Barrowdale; Heiko Becher; Matthias W. Beckmann; Sabine Behrens; Javier Benitez; Marina Bermisheva; Katarzyna Bialkowska; Ana Blanco; Carl Blomqvist; Natalia V. Bogdanova; Stig E. Bojesen; Bernardo Bonanni; Davide Bondavalli; Ake Borg; Hiltrud Brauch; Hermann Brenner; Ignacio Briceno; Annegien Broeks; Sara Y. Brucker; Thomas Brüning; Barbara Burwinkel; Saundra S. Buys; Helen Byers; Trinidad Caldés; Maria A. Caligo; Hans Christiansen; Anne Vibeke Laenkholm; Finn C Nielsen; Mads Thomassen; kConFab Investigators; ABCTB Investigators; EMBRACE Study; GEMO Study Collaborators

doi:10.1038/s41588-020-0609-2

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Haoyu Zhang
, Thomas U. Ahearn
, Julie Lecarpentier
, Daniel Barnes
, Jonathan Beesley
, Guanghao Qi
, Xia Jiang
, Tracy A. O’Mara
, Ni Zhao
, Manjeet K. Bolla
, Alison M. Dunning
, Joe Dennis
, Qin Wang
, Zumuruda Abu Ful
, Kristiina Aittomäki
, Irene L. Andrulis
, Hoda Anton-Culver
, Volker Arndt
, Kristan J. Aronson
, Banu K. Arun

Paul L. Auer, Jacopo Azzollini, Daniel Barrowdale, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Bialkowska, Ana Blanco, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Davide Bondavalli, Ake Borg, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Annegien Broeks, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Helen Byers, Trinidad Caldés, Maria A. Caligo, Hans Christiansen, Anne Vibeke Laenkholm, Finn C Nielsen, Mads Thomassen, kConFab Investigators, ABCTB Investigators, EMBRACE Study, GEMO Study Collaborators

National Cancer Institute
Johns Hopkins University
University of Cambridge
QIMR Berghofer Medical Research Institute
Harvard T.H. Chan School of Public Health
Technion – Israel Institute of Technology
Helsinki University Hospital
Mount Sinai Hospital
University of California
German Cancer Research Center
Queen's University
The University of Texas MD Anderson Cancer Center
Fred Hutchinson Cancer Research Center
University of Wisconsin–Milwaukee
National Cancer Institute of Milan
University Medical Center Hamburg-Eppendorf
University Hospital Erlangen
Spanish Network on Rare Diseases (CIBERER)
Russian Academy of Sciences
Pomeranian Medical University
Fundación Pública Galega de Medicina Xenómica
University Clinical Hospital of Santiago de Compostela
Örebro University Hospital
N.N. Alexandrov Research Institute of Oncology and Medical Radiology
Hannover Medical School
Københavns Universitetshospital
Københavns Universitet
Spanish National Cancer Research Centre
Istituto Europeo di Oncologia
Lund University
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Eberhard Karls University of Tübingen
University of La Sabana
The Netherlands Cancer Institute
Ruhr University Bochum
Heidelberg University
The University of Utah
Manchester University NHS Foundation Trust
San Carlos Clinical Hospital
University Hospital of Pisa
Sjællands Universitetshospital
Rigshospitalet

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Abstract

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype^1–3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10⁻⁸), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	52
Udgave nummer	6
Sider (fra-til)	572-581
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-020-0609-2
Status	Udgivet - jun. 2020

Finansiering

We thank all of the individuals who took part in these studies, and all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out. This project has been funded in part with Federal funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. 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 et 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) (1U19 CA148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research 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 (1U19 CA148065) (DRIVE, part of the GAME-ON initiative). Linkage disequilibrium score regression analysis was supported by grant CA194393. BCAC was 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) and 634935 (BRIDGES)). CIMBA was funded by Cancer Research UK (C12292/A20861 and C12292/A11174). N.C. was funded by NHGRI (1R01 HG010480-01). For a full description of funding and acknowledgments, see the Supplementary Note.

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10.1038/s41588-020-0609-2

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Zhang, H., Ahearn, T. U., Lecarpentier, J., Barnes, D., Beesley, J., Qi, G., Jiang, X., O’Mara, T. A., Zhao, N., Bolla, M. K., Dunning, A. M., Dennis, J., Wang, Q., Ful, Z. A., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., ... GEMO Study Collaborators (2020). Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nature Genetics, 52(6), 572-581. https://doi.org/10.1038/s41588-020-0609-2

@article{d3a76a96ea544f9cb59e1ed0b21d81fc,

title = "Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses",

abstract = "Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1{\textendash}3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 {\texttimes} 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2\% for luminal A-like disease and 37.6\% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1\% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.",

author = "Haoyu Zhang and Ahearn, \{Thomas U.\} and Julie Lecarpentier and Daniel Barnes and Jonathan Beesley and Guanghao Qi and Xia Jiang and O{\textquoteright}Mara, \{Tracy A.\} and Ni Zhao and Bolla, \{Manjeet K.\} and Dunning, \{Alison M.\} and Joe Dennis and Qin Wang and Ful, \{Zumuruda Abu\} and Kristiina Aittom{\"a}ki and Andrulis, \{Irene L.\} and Hoda Anton-Culver and Volker Arndt and Aronson, \{Kristan J.\} and Arun, \{Banu K.\} and Auer, \{Paul L.\} and Jacopo Azzollini and Daniel Barrowdale and Heiko Becher and Beckmann, \{Matthias W.\} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Katarzyna Bialkowska and Ana Blanco and Carl Blomqvist and Bogdanova, \{Natalia V.\} and Bojesen, \{Stig E.\} and Bernardo Bonanni and Davide Bondavalli and Ake Borg and Hiltrud Brauch and Hermann Brenner and Ignacio Briceno and Annegien Broeks and Brucker, \{Sara Y.\} and Thomas Br{\"u}ning and Barbara Burwinkel and Buys, \{Saundra S.\} and Helen Byers and Trinidad Cald{\'e}s and Caligo, \{Maria A.\} and Hans Christiansen and Laenkholm, \{Anne Vibeke\} and Nielsen, \{Finn C\} and Mads Thomassen and \{kConFab Investigators\} and \{ABCTB Investigators\} and \{EMBRACE Study\} and \{GEMO Study Collaborators\}",

year = "2020",

month = jun,

doi = "10.1038/s41588-020-0609-2",

language = "English",

volume = "52",

pages = "572--581",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Zhang, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O’Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Ful, ZA, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Brüning, T, Burwinkel, B, Buys, SS, Byers, H, Caldés, T, Caligo, MA, Christiansen, H, Laenkholm, AV, Nielsen, FC, Thomassen, M, kConFab Investigators, ABCTB Investigators, EMBRACE Study & GEMO Study Collaborators 2020, 'Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses', Nature Genetics, bind 52, nr. 6, s. 572-581. https://doi.org/10.1038/s41588-020-0609-2

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T1 - Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

AU - Zhang, Haoyu

AU - Ahearn, Thomas U.

AU - Lecarpentier, Julie

AU - Barnes, Daniel

AU - Beesley, Jonathan

AU - Qi, Guanghao

AU - Jiang, Xia

AU - O’Mara, Tracy A.

AU - Zhao, Ni

AU - Bolla, Manjeet K.

AU - Dunning, Alison M.

AU - Dennis, Joe

AU - Wang, Qin

AU - Ful, Zumuruda Abu

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Arun, Banu K.

AU - Auer, Paul L.

AU - Azzollini, Jacopo

AU - Barrowdale, Daniel

AU - Becher, Heiko

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bialkowska, Katarzyna

AU - Blanco, Ana

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Bondavalli, Davide

AU - Borg, Ake

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Briceno, Ignacio

AU - Broeks, Annegien

AU - Brucker, Sara Y.

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Buys, Saundra S.

AU - Byers, Helen

AU - Caldés, Trinidad

AU - Caligo, Maria A.

AU - Christiansen, Hans

AU - Laenkholm, Anne Vibeke

AU - Nielsen, Finn C

AU - Thomassen, Mads

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AU - ABCTB Investigators

AU - EMBRACE Study

AU - GEMO Study Collaborators

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N2 - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

AB - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

U2 - 10.1038/s41588-020-0609-2

DO - 10.1038/s41588-020-0609-2

M3 - Journal article

C2 - 32424353

AN - SCOPUS:85085167024

SN - 1061-4036

VL - 52

SP - 572

EP - 581

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Abstract

Finansiering

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