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

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

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.

0007-0920
647-657
Escala-Garcia, Maria
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Guo, Qi
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Dörk, Thilo
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Canisius, Sander
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Keeman, Renske
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Dennis, Joe
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Beesley, Jonathan
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Lecarpentier, Julie
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Bolla, Manjeet K.
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Wang, Qin
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Abraham, Jean
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Andrulis, Irene L.
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Anton-Culver, Hoda
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Arndt, Volker
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Auer, Paul L.
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Beckmann, Matthias W.
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Bernstein, Leslie
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Blomqvist, Carl
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Boeckx, Bram
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Bojesen, Stig E.
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Bonanni, Bernardo
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Børresen-Dale, Anne Lise
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Brauch, Hiltrud
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Brenner, Hermann
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Brentnall, Adam
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Brinton, Louise
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Broberg, Per
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Brock, Ian W.
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Brucker, Sara Y.
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Burwinkel, Barbara
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Caldas, Carlos
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Caldés, Trinidad
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Campa, Daniele
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Canzian, Federico
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Carracedo, Angel
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Carter, Brian D.
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Castelao, Jose E.
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Chang-Claude, Jenny
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Chanock, Stephen J.
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Chenevix-Trench, Georgia
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Cheng, Ting Yuan David
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Chin, Suet Feung
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Clarke, Christine L.
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Durcan, Lorraine
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Maishman, Tom
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Tapper, William J.
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Eccles, Diana M.
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NBCS Collaborators
Escala-Garcia, Maria
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Guo, Qi
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Dörk, Thilo
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Canisius, Sander
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Keeman, Renske
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Dennis, Joe
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Beesley, Jonathan
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Lecarpentier, Julie
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Bolla, Manjeet K.
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Wang, Qin
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Abraham, Jean
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Andrulis, Irene L.
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Anton-Culver, Hoda
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Arndt, Volker
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Auer, Paul L.
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Beckmann, Matthias W.
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Behrens, Sabine
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Benitez, Javier
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Bermisheva, Marina
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Bernstein, Leslie
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Blomqvist, Carl
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Boeckx, Bram
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Bojesen, Stig E.
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Bonanni, Bernardo
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Børresen-Dale, Anne Lise
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Brauch, Hiltrud
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Brenner, Hermann
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Brentnall, Adam
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Brinton, Louise
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Broberg, Per
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Brock, Ian W.
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Brucker, Sara Y.
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Burwinkel, Barbara
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Caldas, Carlos
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Caldés, Trinidad
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Campa, Daniele
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Canzian, Federico
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Carracedo, Angel
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Carter, Brian D.
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Castelao, Jose E.
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Chang-Claude, Jenny
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Chanock, Stephen J.
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Chenevix-Trench, Georgia
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Cheng, Ting Yuan David
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Chin, Suet Feung
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Clarke, Christine L.
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Durcan, Lorraine
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Maishman, Tom
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Tapper, William J.
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Eccles, Diana M.
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Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K., Wang, Qin, Abraham, Jean, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L., Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E., Bonanni, Bernardo, Børresen-Dale, Anne Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W., Brucker, Sara Y., Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Cheng, Ting Yuan David, Chin, Suet Feung, Clarke, Christine L., Durcan, Lorraine, Maishman, Tom, Tapper, William J. and Eccles, Diana M. , NBCS Collaborators (2019) Genome-wide association study of germline variants and breast cancer-specific mortality. British Journal of Cancer, 120 (6), 647-657. (doi:10.1038/s41416-019-0393-x).

Record type: Article

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.

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Accepted/In Press date: 14 January 2019
e-pub ahead of print date: 21 February 2019
Published date: 19 March 2019

Identifiers

Local EPrints ID: 430070
URI: https://eprints.soton.ac.uk/id/eprint/430070
ISSN: 0007-0920
PURE UUID: c4727267-558e-459d-9347-6351e1c15090

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Date deposited: 11 Apr 2019 16:30
Last modified: 11 Apr 2019 16:30

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Contributors

Author: Maria Escala-Garcia
Author: Qi Guo
Author: Thilo Dörk
Author: Sander Canisius
Author: Renske Keeman
Author: Joe Dennis
Author: Jonathan Beesley
Author: Julie Lecarpentier
Author: Manjeet K. Bolla
Author: Qin Wang
Author: Jean Abraham
Author: Irene L. Andrulis
Author: Hoda Anton-Culver
Author: Volker Arndt
Author: Paul L. Auer
Author: Matthias W. Beckmann
Author: Sabine Behrens
Author: Javier Benitez
Author: Marina Bermisheva
Author: Leslie Bernstein
Author: Carl Blomqvist
Author: Bram Boeckx
Author: Stig E. Bojesen
Author: Bernardo Bonanni
Author: Anne Lise Børresen-Dale
Author: Hiltrud Brauch
Author: Hermann Brenner
Author: Adam Brentnall
Author: Louise Brinton
Author: Per Broberg
Author: Ian W. Brock
Author: Sara Y. Brucker
Author: Barbara Burwinkel
Author: Carlos Caldas
Author: Trinidad Caldés
Author: Daniele Campa
Author: Federico Canzian
Author: Angel Carracedo
Author: Brian D. Carter
Author: Jose E. Castelao
Author: Jenny Chang-Claude
Author: Stephen J. Chanock
Author: Georgia Chenevix-Trench
Author: Ting Yuan David Cheng
Author: Suet Feung Chin
Author: Christine L. Clarke
Author: Lorraine Durcan
Author: Tom Maishman
Author: Diana M. Eccles

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