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

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  • kConFab/AOCS Investigators
  • NBCS Collaborators
  • ABCTB Investigators
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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.

OriginalsprogEngelsk
Artikelnummer2
TidsskriftBreast Cancer Research
Vol/bind24
Udgave nummer1
ISSN1465-5411
DOI
StatusUdgivet - dec. 2022

Bibliografisk note

Funding Information:
Open Access funding provided by the National Institutes of Health (NIH) This project has been funded in part with Federal funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. Dr. Nilanjan Chatterjee was supported by NHGRI (1R01 HG010480-01). Dr. Haoyu Zhang was supported by National Cancer Institute (1K99 CA256513). OncoArray genotyping was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l'Économie, de la Science et de l'Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1 U19 CA 148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control–Ministry of Health and Welfare (Republic of Korea) (1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837). iCOGS genotyping was funded by the European Union (HEALTH-F2-2009–223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174]), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Ministère de l'Économie, Innovation et Exportation du Québec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. A full description of the funding is provided in the Additional file : Funding and Acknowledgement.

Publisher Copyright:
© 2021, The Author(s).

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