Common variants in breast cancer risk loci predispose to distinct tumor subtypes.
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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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Funder: Genome Canada and the Canadian Institutes of Health Research
Funder: Génome Québec; doi: http://dx.doi.org/10.13039/100013062
Funder: Foundation for the National Institutes of Health; doi: http://dx.doi.org/10.13039/100000009
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: http://dx.doi.org/10.13039/100002645
Funder: National Health and Medical Research Council
Funder: Deutsche Kinderkrebsstiftung; doi: http://dx.doi.org/10.13039/501100007311
Funder: European Union
Funder: National Institutes of Health; doi: http://dx.doi.org/10.13039/100000002
Funder: National Cancer Institute
Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024
Funder: Susan G. Komen for the Cure, Komen Wyoming Affiliate; doi: http://dx.doi.org/10.13039/100005987
Funder: Ovarian Cancer Research Fund; doi: http://dx.doi.org/10.13039/100001282
Funder: National Cancer Institute (NCI)
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1465-542X