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

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@article{691f412c093d4c45b009a67de9e4b946,
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.",
keywords = "Bayes Theorem, Breast Neoplasms/genetics, Chromosomes, Human, Pair 7, European Continental Ancestry Group/genetics, Female, Genetic Variation, Genome-Wide Association Study, Humans, Prognosis, Proportional Hazards Models, Receptors, Estrogen/genetics",
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 Henrik Flyger and Nielsen, {Sune F} and Nordestgaard, {B{\o}rge G} and {NBCS Collaborators}",
year = "2019",
month = "3",
doi = "10.1038/s41416-019-0393-x",
language = "English",
volume = "120",
pages = "647--657",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "6",

}

RIS

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 - 2019/3

Y1 - 2019/3

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.

KW - Bayes Theorem

KW - Breast Neoplasms/genetics

KW - Chromosomes, Human, Pair 7

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Prognosis

KW - Proportional Hazards Models

KW - Receptors, Estrogen/genetics

UR - http://www.scopus.com/inward/record.url?scp=85061925826&partnerID=8YFLogxK

U2 - 10.1038/s41416-019-0393-x

DO - 10.1038/s41416-019-0393-x

M3 - Journal article

VL - 120

SP - 647

EP - 657

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 6

ER -

ID: 56652977