Overall, our results suggest that increasing levels of testosterone, BT, estradiol and DHEAS may increase the risk of overall BC and/or ER+ (postmenopausal) BC risk, consistent with results from observational studies. For the remaining hormones, we found some suggestive associations but also acknowledge the possibility of weak instrument bias and the need for better genetic instruments. Our study provides new insights into the role of sex steroid hormones in BC risk using MR and may inform the eventual development of interventions aimed at BC prevention.
17OHP: 17-Hydroxyprogesterone; ALDO: Aldosterone; ANDRO: Androstenedione; AR: Androgen receptor; BC: Breast cancer; BCAC : Breast Cancer Association Consortium; BT: Bioavailable testosterone; CIMBA: Consortium of Investigators of Modifiers of BRCA1/2; CORNET: CORtisol NETwork; CORT: Cortisol; DHEA: Dehydroepiandrosterone; DHEAS: Dehydroepiandrosterone sulphate; DRIVE: Discovery, Biology and Risk of Inherited Variants in Breast Cancer Consortium; E2: Estradiol; ECLIA: Electrochemiluminescence immunoassay; ER: Oestrogen receptor; HER2: Human epidermal growth factor receptor 2; HR: Hazard ratio; HRT: Hormone replacement therapy; IQR: Interquartile; IVW: Inverse variance weighted; LD: Linkage disequilibrium; LDSC: Linkage disequilibrium score regression; LM-MS/MS: Liquid chromatography-tandem mass spectrometry; MR: Mendelian randomization; MR-RAPS: MR robust adjusted profile score; OR: Odds ratio; PR: Progesterone receptor; PROG: Progesterone; RCT : Randomized controlled trial; SD: Standard deviation; SHBG: Sex hormonebinding globulin; SNP: Single nucleotide polymorphism; TNBC: Triple-negative breast cancer; TT: Total testosterone.
AN and CLR were funded by Cancer Research UK (C18281/A29019, CLR). RCR is a de Pass Vice Chancellor Research Fellow at the University of Bristol. AN and SK are currently supported by a UK Research and Innovation Future Leaders Fellowship (UKRI FLF) to SK (MR/T043202/1).
Availability of data and materials
Summary statistics for total testosterone, bioavailable testosterone and SHBG are available at: https://www.ebi.ac.uk/gwas/publications/32042192. Summary statistics for cortisol are available at: https://datashare.ed.ac.uk/handle/10283/3836. Summary statistics for estradiol, androstenedione, aldosterone, progesterone and 17-hydroxyprogesterone are not publicly available to preserve confidentiality or because they were used under license but access to some of the data may be provided upon contact of the study's corresponding author. Summary statistics for breast cancer incidence are available at https://bcac.ccge.medschl.cam.ac.uk/bcacdata/.
Ethics approval and consent to participate
UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC), which covers the UK. Both LIFE-Adult and LIFE-Heart meet the ethical standards of the Declaration of Helsinki. The Ethics Committee of the Medical Faculty of the University Leipzig (Leipzig, Germany) has approved both studies (LIFE-Adult, Registration No. 263-2009-14122009; LIFE-Heart, Registration No. 276e2005). All participants of CORNET provided written informed consent, and studies were approved by local Research Ethics Committees and/or Institutional Review Boards. All participating studies from BCAC were approved by their appropriate ethics or institutional review board, and all participants provided informed consent.
Consent for publication
Breast Cancer Res. 2022;24(66) © 2022 BioMed Central, Ltd.
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