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

NBCS Collaborators

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
Pages (from-to)647-657
Number of pages11
JournalBritish journal of cancer
Volume120
Issue number6
DOIs
StatePublished - Mar 19 2019

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Genome-Wide Association Study
Breast Neoplasms
Mortality
Meta-Analysis
Long Noncoding RNA
Confidence Intervals
Genes
Chromosomes, Human, Pair 7
Multigene Family
Proportional Hazards Models
Estrogen Receptors
Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Genome-wide association study of germline variants and breast cancer-specific mortality. / NBCS Collaborators.

In: British journal of cancer, Vol. 120, No. 6, 19.03.2019, p. 647-657.

Research output: Contribution to journalArticle

@article{9ade4481828b413d8ad42887e11dc77e,
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 ~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 Steven Hart and Vachon, {Celine M}",
year = "2019",
month = "3",
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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 - Hart, Steven

AU - Vachon, Celine M

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.

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U2 - 10.1038/s41416-019-0393-x

DO - 10.1038/s41416-019-0393-x

M3 - Article

C2 - 30787463

AN - SCOPUS:85061925826

VL - 120

SP - 647

EP - 657

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 6

ER -