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

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

doi:10.1038/s41416-019-0393-x

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

Maria Escala-Garcia
, Qi Guo
, Thilo Dörk
, Sander Canisius
, Renske Keeman
, Joe Dennis
, Jonathan Beesley
, Julie Lecarpentier
, Manjeet K Bolla
, Qin Wang
, Jean Abraham
, Irene L Andrulis
, Hoda Anton-Culver
, Volker Arndt
, Paul L Auer
, Matthias W Beckmann
, Sabine Behrens
, Javier Benitez
, Marina Bermisheva
, Leslie Bernstein

Carl Blomqvist, Bram Boeckx, Stig E Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Adam Brentnall, Louise Brinton, Per Broberg, Ian W Brock, Sara Y Brucker, Barbara Burwinkel, Carlos Caldas, Trinidad Caldés, Daniele Campa, Federico Canzian, Angel Carracedo, Brian D Carter, Jose E Castelao, Jenny Chang-Claude, Stephen J Chanock, Georgia Chenevix-Trench, Ting-Yuan David Cheng, Suet-Feung Chin, Christine L Clarke, Emilie Cordina-Duverger, Fergus J Couch, David G Cox, Nick Orr, NBCS Collaborators

School of Medicine, Dentistry and Biomedical Sciences

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

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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
Early online date	21 Feb 2019
DOIs	https://doi.org/10.1038/s41416-019-0393-x
Publication status	Published - 19 Mar 2019

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Genome-wide association study of germline variants and breast cancer-specific mortality
Copyright 2019 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.04 MBLicence: CC BY

Cite this

Escala-Garcia, M., Guo, Q., Dörk, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M. K., Wang, Q., Abraham, J., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., ... NBCS Collaborators (2019). Genome-wide association study of germline variants and breast cancer-specific mortality. British Journal of Cancer, 120(6), 647-657. https://doi.org/10.1038/s41416-019-0393-x

@article{a9081d8117594221a883bfc862a6d10d,

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 = "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 Anne-Lise B{\o}rresen-Dale 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 Suet-Feung Chin and Clarke, \{Christine L\} and Emilie Cordina-Duverger and Couch, \{Fergus J\} and Cox, \{David G\} and Nick Orr and \{NBCS Collaborators\}",

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",

}

Escala-Garcia, M, Guo, Q, Dörk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldés, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, T-YD, Chin, S-F, Clarke, CL, Cordina-Duverger, E, Couch, FJ, Cox, DG, Orr, N & NBCS Collaborators 2019, 'Genome-wide association study of germline variants and breast cancer-specific mortality', British Journal of Cancer, vol. 120, no. 6, pp. 647-657. https://doi.org/10.1038/s41416-019-0393-x

TY - JOUR

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

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 - Orr, Nick

AU - NBCS Collaborators

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.

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

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