Genome-wide association study of germline variants and breast cancer-specific mortality

NBCS Collaborators

doi:10.1038/s41416-019-0393-x

Genome-wide association study of germline variants and breast cancer-specific mortality

NBCS Collaborators

Antoni van Leeuwenhoek Hospital
University of Cambridge
Hannover Medical School
Queensland Institute of Medical Research
Cambridge Experimental Cancer Medicine Centre
Cambridge University Hospitals NHS Foundation Trust
University of Toronto
University of California at Irvine
German Cancer Research Center
Fred Hutchinson Cancer Research Center
University of Wisconsin-Milwaukee
Friedrich-Alexander University Erlangen-Nürnberg
Biomedical Network on Rare Diseases (CIBERER)
Center for Biomedical Network Research on Rare Diseases (CIBERER)
Russian Academy of Sciences
City of Hope National Medical Center
University of Helsinki
Örebro University
Flanders Institute for Biotechnology
KU Leuven
University of Copenhagen
IRCCS Istituto Europeo di Oncologia - Milano
University of Oslo
Robert Bosch Foundation
University of Tübingen
Queen Mary University of London
National Institutes of Health
Lund University
University of Sheffield
Heidelberg University
Royal Marsden Hospital
Hospital Clínico San Carlos de Madrid
University of Pisa
Instituto de Investigación Sanitaria de Santiago de Compostela
University of Santiago de Compostela
King Abdulaziz University
American Cancer Society
Oncology and Genetics Unit
University of Hamburg
Roswell Park Cancer Institute
University of Sydney
Institut national de la santé et de la recherche médicale
Mayo Clinic
Imperial College London
Centre de Recherche en Cancérologie de Lyon
Karolinska Institutet
Leiden University
University of Warwick
University of Southampton
University of Westminster
Brigham and Women's Hospital
Harvard University
Leipzig University
University of Manchester
Manchester University NHS Foundation Trust
University of Edinburgh
Cancer Research UK Program
University of California at San Diego
Royal Marsden NHS Foundation Trust
Heraklion University Hospital
Cancer Council Victoria
Centre for Epidemiology and Biostatistics
Monash University
University of Utah
University of Oulu
University of Cologne
University of Southern California
University of Massachusetts
Wythenshawe Hospital
University of Eastern Finland
Saarland Cancer Registry
Erasmus University Rotterdam
University of Oxford
Cancer Prevention Institute of California
Stanford University
Tampere University
Pomeranian Medical University in Szczecin
University of Galway
Ufa University of Science and Technology
Evangelical Clinics of Bonn
University of Hawai'i at Mānoa
Technion-Israel Institute of Technology
Tianjin Medical University
University of Washington
Maria Sklodowska-Curie Institute of Oncology
German Breast Group
Fondazione IRCCS Istituto Nazionale dei Tumori
Alfred Health
Ludwig Maximilian University of Munich
University Health Network
Université Paris Cité
University of California at Davis
Queen's University Belfast
University of New Mexico
Hospital Monte Naranco
Hospital Universitario Puerta de Hierro Majadahonda
FIRC Institute of Molecular Oncology
King's College London
Laboratory of Cancer Genetics and Tumour Biology
University College London Hospitals NHS Foundation Trust
University Hospital of Larissa
Case Western Reserve University
Hunter New England Health
University of Newcastle
Université Laval
Department of Clinical Pathology
University of British Columbia
Instituto Português de Oncologia do Porto Francisco Gentil E.P.E.
University of Porto
Columbia University
University of Birmingham
Universidad Javeriana
Frauenklinik der Stadtklinik Baden-Baden
Department of Gynecology and Obstetrics
University of California at Los Angeles

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

54 Scopus citations

Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 ⁻⁸ . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 ⁻⁷ , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 ⁻⁷ , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Original language	English
Pages (from-to)	647-657
Number of pages	11
Journal	British Journal of Cancer
Volume	120
Issue number	6
DOIs	https://doi.org/10.1038/s41416-019-0393-x
State	Published - Mar 19 2019

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10.1038/s41416-019-0393-x

Cite this

@article{85474f0343654caf884621027f93aae6,

title = "Genome-wide association study of germline variants and breast cancer-specific mortality",

abstract = " Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using \textasciitilde{}10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7\%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95\% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11\%, P = 1.38 × 10 −7 , HR = 1.27, 95\% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15\% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.",

author = "\{NBCS Collaborators\} and Maria Escala-Garcia and Qi Guo and Thilo D{\"o}rk and Sander Canisius and Renske Keeman and Joe Dennis and Jonathan Beesley and Julie Lecarpentier and Bolla, \{Manjeet K.\} and Qin Wang and Jean Abraham and Andrulis, \{Irene L.\} and Hoda Anton-Culver and Volker Arndt and Auer, \{Paul L.\} and Beckmann, \{Matthias W.\} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Leslie Bernstein and Carl Blomqvist and Bram Boeckx and Bojesen, \{Stig E.\} and Bernardo Bonanni and B{\o}rresen-Dale, \{Anne Lise\} and Hiltrud Brauch and Hermann Brenner and Adam Brentnall and Louise Brinton and Per Broberg and Brock, \{Ian W.\} and Brucker, \{Sara Y.\} and Barbara Burwinkel and Carlos Caldas and Trinidad Cald{\'e}s and Daniele Campa and Federico Canzian and Angel Carracedo and Carter, \{Brian D.\} and Castelao, \{Jose E.\} and Jenny Chang-Claude and Chanock, \{Stephen J.\} and Georgia Chenevix-Trench and Cheng, \{Ting Yuan David\} and Chin, \{Suet Feung\} and Clarke, \{Christine L.\} and Emilie Cordina-Duverger and Couch, \{Fergus J.\} and Cox, \{David G.\} and Daly, \{Mary B.\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = mar,

day = "19",

doi = "10.1038/s41416-019-0393-x",

language = "English",

volume = "120",

pages = "647--657",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "6",

}

TY - JOUR

T1 - Genome-wide association study of germline variants and breast cancer-specific mortality

AU - NBCS Collaborators

AU - Escala-Garcia, Maria

AU - Guo, Qi

AU - Dörk, Thilo

AU - Canisius, Sander

AU - Keeman, Renske

AU - Dennis, Joe

AU - Beesley, Jonathan

AU - Lecarpentier, Julie

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Abraham, Jean

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Auer, Paul L.

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bernstein, Leslie

AU - Blomqvist, Carl

AU - Boeckx, Bram

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Børresen-Dale, Anne Lise

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Brentnall, Adam

AU - Brinton, Louise

AU - Broberg, Per

AU - Brock, Ian W.

AU - Brucker, Sara Y.

AU - Burwinkel, Barbara

AU - Caldas, Carlos

AU - Caldés, Trinidad

AU - Campa, Daniele

AU - Canzian, Federico

AU - Carracedo, Angel

AU - Carter, Brian D.

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Chenevix-Trench, Georgia

AU - Cheng, Ting Yuan David

AU - Chin, Suet Feung

AU - Clarke, Christine L.

AU - Cordina-Duverger, Emilie

AU - Couch, Fergus J.

AU - Cox, David G.

AU - Daly, Mary B.

PY - 2019/3/19

Y1 - 2019/3/19

N2 - Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

AB - Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

UR - https://www.scopus.com/pages/publications/85061925826

U2 - 10.1038/s41416-019-0393-x

DO - 10.1038/s41416-019-0393-x

M3 - Article

C2 - 30787463

SN - 0007-0920

VL - 120

SP - 647

EP - 657

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 6

ER -

Genome-wide association study of germline variants and breast cancer-specific mortality

Abstract

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