Common variants in breast cancer risk loci predispose to distinct tumor subtypes
Common variants in breast cancer risk loci predispose to distinct tumor subtypes
BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.
METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.
RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.
CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Breast cancer, Common breast cancer susceptibility variants, Etiologic heterogeneity, Genetic predisposition
Ahearn, Thomas
c3ee2477-53ca-4e2a-bc56-9d75e567155f
Zhang, Haoyu
73010046-df4a-4e67-9831-c79ab96ff80c
Michailidou, Kyriaki
3998b901-962f-4233-b277-483ca6e195b6
Milne, Roger L.
387456b7-771b-4533-85c8-006c67db7e36
Bolla, Manjeet K.
26287bbe-c2ce-46ae-b8a2-ba0b49617337
Dennis, Joe
bd305c84-d968-4946-b154-a5bedb469210
et al.,
96c90377-641f-4276-9d09-6968e3f36258
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
4 January 2022
Ahearn, Thomas
c3ee2477-53ca-4e2a-bc56-9d75e567155f
Zhang, Haoyu
73010046-df4a-4e67-9831-c79ab96ff80c
Michailidou, Kyriaki
3998b901-962f-4233-b277-483ca6e195b6
Milne, Roger L.
387456b7-771b-4533-85c8-006c67db7e36
Bolla, Manjeet K.
26287bbe-c2ce-46ae-b8a2-ba0b49617337
Dennis, Joe
bd305c84-d968-4946-b154-a5bedb469210
et al.,
96c90377-641f-4276-9d09-6968e3f36258
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Ahearn, Thomas, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L., Bolla, Manjeet K., Dennis, Joe and et al.,
,
NBCS Collaborators, ABCTB Investigators and AOCS Investigators
(2022)
Common variants in breast cancer risk loci predispose to distinct tumor subtypes.
Breast Cancer Research, 24 (1), [2].
(doi:10.1186/s13058-021-01484-x).
Abstract
BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.
METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.
RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.
CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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Accepted/In Press date: 2 November 2021
Published date: 4 January 2022
Keywords:
Breast cancer, Common breast cancer susceptibility variants, Etiologic heterogeneity, Genetic predisposition
Identifiers
Local EPrints ID: 452666
URI: http://eprints.soton.ac.uk/id/eprint/452666
ISSN: 1465-5411
PURE UUID: 5d81a0ce-183b-40ed-a335-b107daceb159
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Date deposited: 11 Dec 2021 11:35
Last modified: 17 Mar 2024 06:57
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Contributors
Author:
Thomas Ahearn
Author:
Haoyu Zhang
Author:
Kyriaki Michailidou
Author:
Roger L. Milne
Author:
Manjeet K. Bolla
Author:
Joe Dennis
Author:
et al.
Corporate Author: NBCS Collaborators
Corporate Author: ABCTB Investigators
Corporate Author: AOCS Investigators
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