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

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
Breast cancer germline susceptibility variants frequently show heterogeneity in risk by tumor estrogen receptor (ER) status. We performed a genome-wide association study including 133,384 cases and 113,789 controls, along with 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 ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade. We identified 32 novel susceptibility loci (P<5.0x10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed significant associations (p<0.05) in opposite directions between luminal- and non-luminal subtypes. In-silico analyses showed these 5 loci overlapped with cell-specific enhancer profiles that differed between normal luminal and basal mammary cell lines. The genetic correlations between five intrinsic-like subtypes ranged from 0.37 to 0.89. These findings provide a better understanding of genetic predisposition of breast cancer subtypes and inform the development of subtype-specific polygenic risk scores.
1061-4036
572–581
Zhang, Haoyu
73010046-df4a-4e67-9831-c79ab96ff80c
Ahearn, Thomas U.
d39b659c-4972-4295-8553-2a441143878c
Lecarpentier, Julie
b47aa9ae-5d41-49ee-b65c-b08b38daf800
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
et al.
Zhang, Haoyu
73010046-df4a-4e67-9831-c79ab96ff80c
Ahearn, Thomas U.
d39b659c-4972-4295-8553-2a441143878c
Lecarpentier, Julie
b47aa9ae-5d41-49ee-b65c-b08b38daf800
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23

Zhang, Haoyu, Ahearn, Thomas U. and Lecarpentier, Julie , et al. (2020) Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nature Genetics, 52 (6), 572–581. (doi:10.1038/s41588-020-0609-2).

Record type: Article

Abstract

Breast cancer germline susceptibility variants frequently show heterogeneity in risk by tumor estrogen receptor (ER) status. We performed a genome-wide association study including 133,384 cases and 113,789 controls, along with 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 ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade. We identified 32 novel susceptibility loci (P<5.0x10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed significant associations (p<0.05) in opposite directions between luminal- and non-luminal subtypes. In-silico analyses showed these 5 loci overlapped with cell-specific enhancer profiles that differed between normal luminal and basal mammary cell lines. The genetic correlations between five intrinsic-like subtypes ranged from 0.37 to 0.89. These findings provide a better understanding of genetic predisposition of breast cancer subtypes and inform the development of subtype-specific polygenic risk scores.

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Discovery_SNPs_paper_09052019 - Accepted Manuscript
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More information

Accepted/In Press date: 23 January 2020
e-pub ahead of print date: 18 May 2020

Identifiers

Local EPrints ID: 444258
URI: http://eprints.soton.ac.uk/id/eprint/444258
ISSN: 1061-4036
PURE UUID: f2dce79d-d474-4d8b-ad80-fcde8acc9910
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 06 Oct 2020 21:06
Last modified: 10 Jan 2022 05:48

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Contributors

Author: Haoyu Zhang
Author: Thomas U. Ahearn
Author: Julie Lecarpentier
Author: Diana Eccles ORCID iD
Corporate Author: et al.

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