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

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Zhang, Haoyu 
Michailidou, Kyriaki 
Milne, Roger L 
Bolla, Manjeet K 


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.


Funder: Genome Canada and the Canadian Institutes of Health Research

Funder: Génome Québec; doi:

Funder: Foundation for the National Institutes of Health; doi:

Funder: Center for Inherited Disease Research

Funder: Cancer Research UK

Funder: Odense University Hospital Research Foundation

Funder: National R&D Program for Cancer Control–Ministry of Health and Welfare

Funder: Italian Association for Cancer Research

Funder: Carol M. Baldwin Breast Cancer Research Fund; doi:

Funder: National Health and Medical Research Council

Funder: Deutsche Kinderkrebsstiftung; doi:

Funder: European Union

Funder: National Institutes of Health; doi:

Funder: National Cancer Institute

Funder: Canadian Institutes of Health Research; doi:

Funder: Susan G. Komen for the Cure, Komen Wyoming Affiliate; doi:

Funder: Ovarian Cancer Research Fund; doi:

Funder: National Cancer Institute (NCI)


Research Article, Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants

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Breast Cancer Res

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Springer Science and Business Media LLC
Cancer Research UK (CRUK-A16563)