Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

ABCTB Investigators; HEBON Investigators; BCFR Investigators; OCGN Investigators; GEMO Study Collaborators; EMBRACE Collaborators; GC-HBOC study Collaborators

doi:10.1002/gepi.22288

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC study Collaborators

Clinical Departments

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

32 Scopus citations

Abstract

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Original language	English
Pages (from-to)	442-468
Number of pages	27
Journal	Genetic Epidemiology
Volume	44
Issue number	5
DOIs	https://doi.org/10.1002/gepi.22288
State	Published - 1 Jul 2020

Funding

Funders	Funder number
Finnish Cancer Foundation
Agence Nationale de la Recherche
Clinical Genetics Branch, NCI
Sundhed og Sygdom, Det Frie Forskningsråd
NKR
Itä-Suomen Yliopisto
US Government or the BCFR
Stefanie Spielman Breast Bank
Kentucky Cancer Registry
AMGEN
Landspítali Háskólasjúkrahús
Florida Cancer Data System
National Breast Cancer Foundation
PALGA
Netherlands Cancer Registry
National Research Foundation of Korea
Federal Agency for Scientific Organizations
Ohio State University Comprehensive Cancer Center
Guy's and St. Thomas
Gentofte Hospital
Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum
Basic Research Laboratory
Dutch Prevention Funds
National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Government of Canada
Genome Canada
Leids Universitair Medisch Centrum
Avon Foundation for Women
Rudolf Bartling Foundation
Stockholms Läns Landsting
Sheffield Experimental Cancer Medicine Centre
Breast Cancer Research Foundation
Ligue Contre le Cancer
Agency for Science, Technology and Research
Cancer Council Victoria
IKNL
CANCER RESEARCH INSTITUTE
Kuopion Yliopistollinen Sairaala
Tennessee Department of Health
University of Crete
Baden-Württemberg Stiftung
Institut national de la santé et de la recherche médicale
Louisiana Tumor Registry
Agency for Science, Technology, and Research of Singapore
NIHR Comprehensive Biomedical Research Centre
National University of Singapore
National Cancer Research Network
Helsinki University Hospital Research Fund
Génome Québec
LK Research Funds
Gustav V Jubilee foundation and Bert von Kantzows foundation
BCFR
Australian National Breast Cancer Foundation
Fondation du cancer du sein du Québec
Agence Nationale de S?curit?
Niedersächsischen Krebsgesellschaft
Ministère de l'Économie, de la Science et de l'Innovation - Québec
Institut Catal?
Icelandic Association
Netherlands Comprehensive Cancer Organisation
NC-BCFR
Royal Marsden/Institute of Cancer Research NIHR
BCFR-PA
Breast Cancer Now
World Cancer Research Fund
Overlæge Johan Boserup og Lise Boserups Legat
Ministerio de Economía y Competitividad
PEME I + D e I + D Suma del Plan Gallego de Investigaci?n
COGS
Rijksuniversiteit Groningen
Albert Einstein Cancer Center
Dietmar-Hopp Foundation
South Carolina Central Cancer Registry
Fonds Wetenschappelijk Onderzoek
Cancerfonden
Finnish Cancer Organizations
Cancer Council South Australia
Institute of the Ruhr University Bochum
Centre International de Recherche sur le Cancer
The Cancer Foundation of Western Australia
Helmholtz Society
Naval Medical Research Center
Dutch ZON (Zorg Onderzoek Nederland
California Department of Public Health
European Regional Development Fund and Free State of Saxony
Associazione Italiana per la Ricerca sul Cancro
Radboud Universitair Medisch Centrum
Oulun Yliopisto
Association for International Cancer Research
Ministerie van Volksgezondheid, Welzijn en Sport
Oak foundation
International Psychogeriatric Association
Health Research Fund
National Research Council
Fundación Mutua Madrileña
Deutsche Gesetzliche Unfallversicherung
National University Cancer Institute, Singapore
Institut Gustave-Roussy
North Carolina Division of Public Health
Cancer Foundation of Western Australia
Mississippi Cancer Registry
Novartis
Fundación Cellex
Karolinska Institutet
Japan Agency for Medical Research and Development
National Heart, Lung, and Blood Institute
Cancer Research Malaysia
Virginia Department of Health
National Cancer Institute of Thailand
Office of Cancer Surveillance
Ministerio de Sanidad, Servicios Sociales e Igualdad
American Cancer Society
Stavros Niarchos Foundation
Dr. Ralph and Marian Falk Medical Research Trust
North Carolina Central Cancer Registry
Georgia Comprehensive Cancer Registry
David F. and Margaret T. Grohne Family Foundation
Claudia von Schilling Foundation for Breast Cancer Research
National Program of Cancer Registries
VicHealth	396414, 209057
Cancer Council Western Australia
Minist?re de l??
Cancer Council Tasmania
Victorian Cancer Registry
Cancer UK
University of Cambridge
Guy's and St Thomas?
Xunta de Galicia
Cancer Council NSW
Cancer Institute NSW
North Carolina University Cancer Research Fund
BBMRI
Deutsche Krebshilfe
Maastricht Universitair Medisch Centrum
German Cancer Research Center
Fondation de France
Komen Foundation for the Cure
University Medical Center Utrecht
Finnish Cancer Society
German Academic Exchange Program
Gesellschaft der Freunde der Medizinischen Hochschule Hannover
Hellenic Health Foundation
Institut National de la Sant?
King's College London
Manchester Biomedical Research Centre
Netherlands Cancer Institute
Pfizer
Cancer Australia
Institute of Biomedical Sciences, Academia Sinica
Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail
Universitätsklinikum Erlangen
Arkansas Department of Health
Vetenskapsrådet
Korea Health Industry Development Institute
Ministero dello Sviluppo Economico
ERC-2011-294576
Alexander von Humboldt-Stiftung
Sigrid Juséliuksen Säätiö
Horizon 2020
de l'Environnement et du Travail
Cancer Council Queensland
UK Research and Innovation
Division of Cancer Epidemiology and Genetics, National Cancer Institute	NO2‐CP‐11019‐50
Seventh Framework Programme	HEALTH‐F2‐2009‐223175, 669026, 634935
National Institute of Environmental Health Sciences	Z01-ES049030
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	12-054, 17‐00‐00171, 110005, 2014‐187, 18‐515‐45012, NWO 91109024, 184.021.007/CP46, 184.021.007, 19‐515‐25001
California Department of Health	N01CN25403
Cancer Research UK	C5047/A10692, C5047/A8384, C1287/A16563, C12292/A11174, C1287/A10118, C1281/A12014, C1287/A10710, C8197/A16565, C5047/A15007
National Institute on Handicapped Research	110837, PGfAR 0707-10031
Biomedical Research Council	05/1/21/19/425, Z01-ES049033, Z01-ES044005, Z01-ES102245
Red Tem?tica de Investigaci?n Cooperativa en C?ncer	PI12/00070, PI11/00923
Institut National du Cancer	AOR 01 082, 2013-1-BCB-01-ICH-1
Fondation ARC pour la Recherche sur le Cancer	PJA 20151203365
Medical Research Council	MR/M012190/1, MC_PC_14105
LIFE?Leipzig Research Centre for Civilization Diseases	14575/2470, 713-241202, 01KW9976/8, 01KW0114, 01KW9975/5, 01KW9977/0, 14505/2470
Fru Berta Kamprads Stiftelse	CA128931, CA140286, CA177150, CA97396
UCLH Biomedical Research Centre	R01CA47305, R01 CA47147
New Hampshire	R01 CA89085, P50 CA125183, R01CA69664, D43 TW009112
Salut and Autonomous Government of Catalonia	2014SGR338, SIOP-06-258-01-COUN, 2009SGR290
Center of Excellence	251314
Canadian Cancer Society	313404
Ministry of Education, Culture, Sports, Science and Technology	26253041, UM1 CA176726, P01 CA87969, 170150181, UM1 CA186107
Minister of Science and Higher Education	002/RID/2018/19
European Commission	SHS-E-SP 18-015
Canadian Institutes of Health Research	GPH‐129344
Consejo Nacional de Ciencia y Tecnolog?a	SALUD-2002-C01-7462
Susan G. Komen for the Cure	FAS0703856
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"	CA176785, CA116201, CA116167, CA192393
Breast Cancer Campaign	2013PR044, DDHK 2004-3124, 2010PR62, DDHK 2009-4318
Lon V Smith Foundation	LVS39420
Spanish Health Research Foundation	INT16/00154, INT15/00070, INT17/00133
Science et Innovation du Qu?bec	PSR-SIIRI-701
Ministry of Health and Welfare	1020350, HI16C1127, 1420190, 1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098
National Cancer Institute	K24CA169004, R01CA120120, N02-CP-65504, N02-CP-21013-63
National Cancer Center	15ck0106177h0001
Innovaci?n Tecnol?gica de la Conseller?a de Industria de la Xunta de Galicia, Spain	EC11-192
National Institutes of Health	1U19 CA148537, 1U19 CA148112, 1U19 CA148065, CA128978
Medical Research and Materiel Command	DAMD17-01-1-0729
Bundesministerium für Bildung und Forschung	RUS08/017
Centro de Investigaci?n Biom?dica en Red de Enferemdades Raras CIBERER	ER17P1AC7112/2018
ISCIII RETIC	C8221/A19170, RD06/0020, C570/A16491
Susan G. Komen	R01CA64277, UMCA182910, R01CA148667, SAC110026, R37CA70867
Division of Cancer Prevention, National Cancer Institute	C1275/C22524, C1275/A15956, C1275/A11699, C1275/A19187
Instituto de Salud Carlos III	PI13/01136
Breast Cancer Research Trust	Z01-CP010119
Robert and Kate Niehaus Clinical Cancer Genetics Initiative	CRN-87521
Manchester NIHR Biomedical research center Manchester	P30-CA-51008, NKFI_OTKA K-112228, IS-BRC-1215-20007, KTIA-OTKA CK-80745
Jess and Mildred Fisher Center for Hereditary Cancer	C18281/A19169
Horizon 2020 Framework Programme	633784, 223175
Academia Sinica	CA58860, CA92044
Breast Cancer Now Tissue Bank	R01 CA092447
Hamburg Cancer Society	01KH0402
Swedish Cancer Foundation	PBZ_KBN_122/P05/2004
U.S. Department of Health and Human Services	HHSN268201100004C, HHSN268201100003C, HHSN271201100004C, HHSN268201100002C, HHSN268201100046C, U19 CA148065-01, HHSN268201100001C
Ministry of Higher Education, Malaysia	UM.C/HlR/MOHE/06, RP046B-15HTM
Hereditary Cancer Research Registry	RC4CA153828
California Breast Cancer Research Fund	U01 CA199277, UM1 CA164917, R01 CA77398, 97-10500
Centers for Disease Control and Prevention	C490/A16561, C490/A10124
Against Breast Cancer Registered Charity	1121258
Instituto de Investigacion Biomedica Galicia Sur	10CSA012E
Ministry of Education, Science and Technology	2012-0000347
Ovarian Cancer Research Fund	UM1 CA164920
University of Oulu Support Foundation	RUL 1997-1505
Dutch Cancer Society	NKI2007‐3756, 2009 4363, NKI 2007-3839, NKI2004‐3088, NKI1998‐1854
FIS	PI13/01162, PI13/00061
South-Eastern Norway Health Authority	39346, 27208
Deutscher Akademischer Austauschdienst	106332, 110828, 110826, 108253, 108419
NIHR Oxford Biomedical Research Centre	C8620/A8372/A15106
Norges Forskningsråd	193387/V50, 193387/H10
Autonomous Government of Galicia	IN607B
National Health and Medical Research Council	400281, 400413, 1074383, 199600
U.S. Department of Defense	W81XWH‐10‐1‐0341
Cancer Registry	AR 72205
Ministry of Health, Labour and Welfare	17015049, 221S0001
K.G. Jebsen Centre for Breast Cancer Research	R01CA100374, 2012-2015, P30 CA68485
Department of Internal Medicine, University of Nebraska Medical Center	70492
European Regional Development Fund	PI13/00285, PI10/01422, PI15/00854, PI16/00563, PIE13/00022
Australian Institute of Health and Welfare	CA098758, CA54281, CA164973, CA63464, CA132839
Biobanking and Biomolecular Resources Research Infrastructure	BBMRI-NL CP16
Komen Foundation	P50 CA058223, U01 CA179715, U54 CA156733
Kreftforeningen	419616-71248-PR-2006-0282
Russian Foundation for Basic Research	17-29-06014, 17-44-020498, 14-04-97088
Suomen Akatemia	250083, 122715
National Center for Advancing Translational Sciences	UL1TR000124

Keywords

GWAS
TWAS
breast cancer subtype
causal gene

UN SDGs

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

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10.1002/gepi.22288

Cite this

@article{2b259ae2820e41a78d59e11ed362256c,

title = "Transcriptome-wide association study of breast cancer risk by estrogen-receptor status",

abstract = "Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.",

keywords = "GWAS, TWAS, breast cancer subtype, causal gene",

author = "{ABCTB Investigators} and {HEBON Investigators} and {BCFR Investigators} and {OCGN Investigators} and {GEMO Study Collaborators} and {EMBRACE Collaborators} and {GC-HBOC study Collaborators} and Helian Feng and Alexander Gusev and Bogdan Pasaniuc and Lang Wu and Jirong Long and Zomoroda Abu-full and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Hoda Anton-Culver and Antoniou, {Antonis C.} and Adalgeir Arason and Volker Arndt and Aronson, {Kristan J.} and Arun, {Banu K.} and Ella Asseryanis and Auer, {Paul L.} and Jacopo Azzollini and Judith Balma{\~n}a and Barkardottir, {Rosa B.} and Barnes, {Daniel R.} and Daniel Barrowdale and Beckmann, {Matthias W.} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Katarzyna Bia{\l}kowska and Ana Blanco and Carl Blomqvist and Bram Boeckx and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Bernardo Bonanni and Ake Borg and Hiltrud Brauch and Hermann Brenner and Ignacio Briceno and Annegien Broeks and Thomas Br{\"u}ning and Barbara Burwinkel and Qiuyin Cai and Trinidad Cald{\'e}s and Caligo, {Maria A.} and Ian Campbell and Sander Canisius and Daniele Campa and Carter, {Brian D.} and Jonathan Carter and Castelao, {Jose E.} and Eitan Friedman",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals, Inc.",

year = "2020",

month = jul,

day = "1",

doi = "10.1002/gepi.22288",

language = "אנגלית",

volume = "44",

pages = "442--468",

journal = "Genetic Epidemiology",

issn = "0741-0395",

publisher = "Wiley-Liss Inc.",

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T1 - Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

AU - ABCTB Investigators

AU - HEBON Investigators

AU - BCFR Investigators

AU - OCGN Investigators

AU - GEMO Study Collaborators

AU - EMBRACE Collaborators

AU - GC-HBOC study Collaborators

AU - Feng, Helian

AU - Gusev, Alexander

AU - Pasaniuc, Bogdan

AU - Wu, Lang

AU - Long, Jirong

AU - Abu-full, Zomoroda

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Antoniou, Antonis C.

AU - Arason, Adalgeir

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Arun, Banu K.

AU - Asseryanis, Ella

AU - Auer, Paul L.

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barkardottir, Rosa B.

AU - Barnes, Daniel R.

AU - Barrowdale, Daniel

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Białkowska, Katarzyna

AU - Blanco, Ana

AU - Blomqvist, Carl

AU - Boeckx, Bram

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Bonanni, Bernardo

AU - Borg, Ake

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Briceno, Ignacio

AU - Broeks, Annegien

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Cai, Qiuyin

AU - Caldés, Trinidad

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Canisius, Sander

AU - Campa, Daniele

AU - Carter, Brian D.

AU - Carter, Jonathan

AU - Castelao, Jose E.

AU - Friedman, Eitan

PY - 2020/7/1

Y1 - 2020/7/1

N2 - Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

AB - Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

KW - GWAS

KW - TWAS

KW - breast cancer subtype

KW - causal gene

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SN - 0741-0395

VL - 44

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JO - Genetic Epidemiology

JF - Genetic Epidemiology

IS - 5

ER -

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Abstract

Funding

Keywords

UN SDGs

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