Breast cancer risk factors and their effects on survival: a Mendelian randomisation study.
Breast cancer risk factors
Breast cancer survival
GWAS Catalog
Lifestyle
Mendelian randomisation
Journal
BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723
Informations de publication
Date de publication:
17 11 2020
17 11 2020
Historique:
received:
15
05
2020
accepted:
25
09
2020
entrez:
17
11
2020
pubmed:
18
11
2020
medline:
23
2
2021
Statut:
epublish
Résumé
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). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33198768
doi: 10.1186/s12916-020-01797-2
pii: 10.1186/s12916-020-01797-2
pmc: PMC7670589
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
327Subventions
Organisme : Cancer Research UK
ID : C1287/A16563
Pays : United Kingdom
Organisme : European Union's Horizon 2020 Research and Innovation Programme
ID : 634935, 633784
Pays : International
Organisme : European Community´s Seventh Framework Programme
ID : HEALTH-F2-2009-223175
Pays : International
Organisme : NCI NIH HHS
ID : U19 CA148537
Pays : United States
Organisme : KWF Kankerbestrijding
ID : 2015-7632
Pays : International
Organisme : Cancer Research UK
ID : C1287/A10118
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : U19 CA148065
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA148112
Pays : United States
Organisme : Cancer Research UK
ID : C1287/A10118
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1287/A10710
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C12292/A11174
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1281/A12014
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5047/A8384
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5047/A15007
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5047/A10692
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C8197/A16565
Pays : United Kingdom
Organisme : CIHR
Pays : Canada
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