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Published in: BMC Medicine 1/2020

01-12-2020 | Breast Cancer | Research article

Breast cancer risk factors and their effects on survival: a Mendelian randomisation study

Authors: Maria Escala-Garcia, Anna Morra, Sander Canisius, Jenny Chang-Claude, Siddhartha Kar, Wei Zheng, Stig E. Bojesen, Doug Easton, Paul D. P. Pharoah, Marjanka K. Schmidt

Published in: BMC Medicine | Issue 1/2020

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Abstract

Background

Observational studies have investigated the association of risk factors with breast cancer prognosis. However, the results have been conflicting and it has been challenging to establish causality due to potential residual confounding. Using a Mendelian randomisation (MR) approach, we aimed to examine the potential causal association between breast cancer-specific survival and nine established risk factors for breast cancer: alcohol consumption, body mass index, height, physical activity, mammographic density, age at menarche or menopause, smoking, and type 2 diabetes mellitus (T2DM).

Methods

We conducted a two-sample MR analysis on data from the Breast Cancer Association Consortium (BCAC) and risk factor summary estimates from the GWAS Catalog. The BCAC data included 86,627 female patients of European ancestry with 7054 breast cancer-specific deaths during 15 years of follow-up. Of these, 59,378 were estrogen receptor (ER)-positive and 13,692 were ER-negative breast cancer patients. For the significant association, we used sensitivity analyses and a multivariable MR model. All risk factor associations were also examined in a model adjusted by other prognostic factors.

Results

Increased genetic liability to T2DM was significantly associated with worse breast cancer-specific survival (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.03–1.17, P value [P] = 0.003). There were no significant associations after multiple testing correction for any of the risk factors in the ER-status subtypes. For the reported significant association with T2DM, the sensitivity analyses did not show evidence for violation of the MR assumptions nor that the association was due to increased BMI. The association remained significant when adjusting by other prognostic factors.

Conclusions

This extensive MR analysis suggests that T2DM may be causally associated with worse breast cancer-specific survival and therefore that treating T2DM may improve prognosis.
Appendix
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Metadata
Title
Breast cancer risk factors and their effects on survival: a Mendelian randomisation study
Authors
Maria Escala-Garcia
Anna Morra
Sander Canisius
Jenny Chang-Claude
Siddhartha Kar
Wei Zheng
Stig E. Bojesen
Doug Easton
Paul D. P. Pharoah
Marjanka K. Schmidt
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2020
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-020-01797-2

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