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Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

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@article{21c3cdc9b6bb421bbf29c10c2c37350d,
title = "Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses",
abstract = "Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.",
keywords = "BRCA1 Protein/genetics, Breast Neoplasms/genetics, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Mutation, Triple Negative Breast Neoplasms/genetics",
author = "Haoyu Zhang and Ahearn, {Thomas U} and Julie Lecarpentier and Daniel Barnes and Jonathan Beesley and Guanghao Qi and Xia Jiang and O'Mara, {Tracy A} and Ni Zhao and Bolla, {Manjeet K} and Dunning, {Alison M} and Joe Dennis and Qin Wang and Ful, {Zumuruda Abu} and Kristiina Aittom{\"a}ki and Andrulis, {Irene L} and Hoda Anton-Culver and Volker Arndt and Aronson, {Kristan J} and Arun, {Banu K} and Auer, {Paul L} and Jacopo Azzollini and Daniel Barrowdale and Heiko Becher and Beckmann, {Matthias W} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Katarzyna Bialkowska and Ana Blanco and Carl Blomqvist and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Bernardo Bonanni and Davide Bondavalli and Ake Borg and Hiltrud Brauch and Hermann Brenner and Ignacio Briceno and Annegien Broeks and Brucker, {Sara Y} and Thomas Br{\"u}ning and Barbara Burwinkel and Buys, {Saundra S} and Helen Byers and Trinidad Cald{\'e}s and Caligo, {Maria A} and Mariarosaria Calvello and Anne-Vibeke Laenkholm and Nielsen, {Finn C} and {kConFab Investigators}",
year = "2020",
month = jun,
doi = "10.1038/s41588-020-0609-2",
language = "English",
volume = "52",
pages = "572--581",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",

}

RIS

TY - JOUR

T1 - Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

AU - Zhang, Haoyu

AU - Ahearn, Thomas U

AU - Lecarpentier, Julie

AU - Barnes, Daniel

AU - Beesley, Jonathan

AU - Qi, Guanghao

AU - Jiang, Xia

AU - O'Mara, Tracy A

AU - Zhao, Ni

AU - Bolla, Manjeet K

AU - Dunning, Alison M

AU - Dennis, Joe

AU - Wang, Qin

AU - Ful, Zumuruda Abu

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Aronson, Kristan J

AU - Arun, Banu K

AU - Auer, Paul L

AU - Azzollini, Jacopo

AU - Barrowdale, Daniel

AU - Becher, Heiko

AU - Beckmann, Matthias W

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bialkowska, Katarzyna

AU - Blanco, Ana

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Bonanni, Bernardo

AU - Bondavalli, Davide

AU - Borg, Ake

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Briceno, Ignacio

AU - Broeks, Annegien

AU - Brucker, Sara Y

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Buys, Saundra S

AU - Byers, Helen

AU - Caldés, Trinidad

AU - Caligo, Maria A

AU - Calvello, Mariarosaria

AU - Laenkholm, Anne-Vibeke

AU - Nielsen, Finn C

AU - kConFab Investigators

PY - 2020/6

Y1 - 2020/6

N2 - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

AB - Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

KW - BRCA1 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Case-Control Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Linkage Disequilibrium

KW - Mutation

KW - Triple Negative Breast Neoplasms/genetics

U2 - 10.1038/s41588-020-0609-2

DO - 10.1038/s41588-020-0609-2

M3 - Journal article

C2 - 32424353

VL - 52

SP - 572

EP - 581

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -

ID: 61974859