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Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Ahearn, T.U. ; Augustinsson, Annelie LU ; Krüger, Ute LU ; Olsson, Håkan LU orcid ; Wagner, Philippe LU and Chatterjee, N. C. (2022) In Breast Cancer Research 24(1).
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.... (More)
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. © 2021, The Author(s). (Less)
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author
; ; ; ; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, Common breast cancer susceptibility variants, Etiologic heterogeneity, Genetic predisposition
in
Breast Cancer Research
volume
24
issue
1
article number
2
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85122468719
  • pmid:34983606
ISSN
1465-5411
DOI
10.1186/s13058-021-01484-x
language
English
LU publication?
yes
id
d8b91032-7d51-462d-b8c6-3c3e5c93c04f
date added to LUP
2022-03-02 15:30:40
date last changed
2022-04-25 18:15:04
@article{d8b91032-7d51-462d-b8c6-3c3e5c93c04f,
  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 &lt; 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 &lt; 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. © 2021, The Author(s).}},
  author       = {{Ahearn, T.U. and Augustinsson, Annelie and Krüger, Ute and Olsson, Håkan and Wagner, Philippe and Chatterjee, N. C.}},
  issn         = {{1465-5411}},
  keywords     = {{Breast cancer; Common breast cancer susceptibility variants; Etiologic heterogeneity; Genetic predisposition}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Breast Cancer Research}},
  title        = {{Common variants in breast cancer risk loci predispose to distinct tumor subtypes}},
  url          = {{http://dx.doi.org/10.1186/s13058-021-01484-x}},
  doi          = {{10.1186/s13058-021-01484-x}},
  volume       = {{24}},
  year         = {{2022}},
}