PMID- 33198768 OWN - NLM STAT- MEDLINE DCOM- 20210222 LR - 20240430 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 18 IP - 1 DP - 2020 Nov 17 TI - Breast cancer risk factors and their effects on survival: a Mendelian randomisation study. PG - 327 LID - 10.1186/s12916-020-01797-2 [doi] LID - 327 AB - 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. FAU - Escala-Garcia, Maria AU - Escala-Garcia M AD - Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. FAU - Morra, Anna AU - Morra A AD - Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. FAU - Canisius, Sander AU - Canisius S AD - Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. AD - Division of Molecular Carcinogenesis, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. FAU - Chang-Claude, Jenny AU - Chang-Claude J AD - Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. AD - University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg (UCCH), Cancer Epidemiology Group, Hamburg, Germany. FAU - Kar, Siddhartha AU - Kar S AD - MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. AD - Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. FAU - Zheng, Wei AU - Zheng W AD - Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. FAU - Bojesen, Stig E AU - Bojesen SE AD - Copenhagen University Hospital, Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark. AD - Copenhagen University Hospital, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark. AD - Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Easton, Doug AU - Easton D AD - Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. AD - Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. FAU - Pharoah, Paul D P AU - Pharoah PDP AD - Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. AD - Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. FAU - Schmidt, Marjanka K AU - Schmidt MK AUID- ORCID: 0000-0002-2228-429X AD - Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. mk.schmidt@nki.nl. AD - Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. mk.schmidt@nki.nl. LA - eng GR - 16563/CRUK_/Cancer Research UK/United Kingdom GR - C1287/A10710/CRUK_/Cancer Research UK/United Kingdom GR - CAPMC/CIHR/Canada GR - C12292/A11174/CRUK_/Cancer Research UK/United Kingdom GR - C5047/A10692/CRUK_/Cancer Research UK/United Kingdom GR - C5047/A8384/CRUK_/Cancer Research UK/United Kingdom GR - R01 CA128978/CA/NCI NIH HHS/United States GR - U19 CA148537/CA/NCI NIH HHS/United States GR - C5047/A15007/CRUK_/Cancer Research UK/United Kingdom GR - U19 CA148065/CA/NCI NIH HHS/United States GR - C1281/A12014/CRUK_/Cancer Research UK/United Kingdom GR - C8197/A16565/CRUK_/Cancer Research UK/United Kingdom GR - 19169/CRUK_/Cancer Research UK/United Kingdom GR - U19 CA148112/CA/NCI NIH HHS/United States GR - C1287/A10118/CRUK_/Cancer Research UK/United Kingdom GR - C1287/A16563/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201117 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 SB - IM MH - Breast Neoplasms/*genetics/mortality MH - Female MH - Humans MH - Mendelian Randomization Analysis/*methods MH - Risk Factors MH - Survival Analysis PMC - PMC7670589 OTO - NOTNLM OT - Breast cancer risk factors OT - Breast cancer survival OT - GWAS Catalog OT - Lifestyle OT - Mendelian randomisation COIS- The authors declare no competing interests. EDAT- 2020/11/18 06:00 MHDA- 2021/02/23 06:00 PMCR- 2020/11/17 CRDT- 2020/11/17 05:44 PHST- 2020/05/15 00:00 [received] PHST- 2020/09/25 00:00 [accepted] PHST- 2020/11/17 05:44 [entrez] PHST- 2020/11/18 06:00 [pubmed] PHST- 2021/02/23 06:00 [medline] PHST- 2020/11/17 00:00 [pmc-release] AID - 10.1186/s12916-020-01797-2 [pii] AID - 1797 [pii] AID - 10.1186/s12916-020-01797-2 [doi] PST - epublish SO - BMC Med. 2020 Nov 17;18(1):327. doi: 10.1186/s12916-020-01797-2.