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

Department of Clinical Medicine

13 Citations (Scopus)

6 Downloads (Pure)

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
Journal	British Journal of Cancer
Volume	120
Issue number	6
Pages (from-to)	647-657
Number of pages	11
ISSN	0007-0920
DOIs	https://doi.org/10.1038/s41416-019-0393-x
Publication status	Published - 2019

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Genome-wide association study of germline variants and breast cancer-specific mortalityFinal published version, 1.04 MBLicence: CC BY

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@article{32551a6ed4144ea1864c291fc8ce4e89,

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 = "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 Henrik Flyger and Nielsen, {Sune F.} and Nordestgaard, {B{\o}rge G.} and {NBCS Collaborators}",

year = "2019",

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

language = "English",

volume = "120",

pages = "647--657",

journal = "The British journal of cancer. Supplement",

issn = "0007-0920",

publisher = "nature publishing group",

number = "6",

}

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 - Flyger, Henrik

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - NBCS Collaborators

PY - 2019

Y1 - 2019

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 - Journal article

C2 - 30787463

AN - SCOPUS:85061925826

SN - 0007-0920

VL - 120

SP - 647

EP - 657

JO - The British journal of cancer. Supplement

JF - The British journal of cancer. Supplement

IS - 6

ER -

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

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