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Epidemiology

Assessing the role of cortisol in cancer: a wide-ranged Mendelian randomisation study

Abstract

Background

Cortisol’s immunosuppressive, obesogenic, and hyperglycaemic effects suggest that it may play a role in cancer development. However, whether cortisol increases cancer risk is not known. We investigated the potential causal association between plasma cortisol and risk of overall and common site-specific cancers using Mendelian randomisation.

Methods

Three genetic variants associated with morning plasma cortisol levels at the genome-wide significance level (P < 5 × 10−8) in the Cortisol Network consortium were used as genetic instruments. Summary-level genome-wide association study data for the cancer outcomes were obtained from large-scale cancer consortia, the UK Biobank, and the FinnGen consortium. Two-sample Mendelian randomisation analyses were performed using the fixed-effects inverse-variance weighted method. Estimates across data sources were combined using meta-analysis.

Results

A standard deviation increase in genetically predicted plasma cortisol was associated with increased risk of endometrial cancer (odds ratio 1.50, 95% confidence interval 1.13–1.99; P = 0.005). There was no significant association between genetically predicted plasma cortisol and risk of other common site-specific cancers, including breast, ovarian, prostate, colorectal, lung, or malignant skin cancer, or overall cancer.

Conclusions

These results indicate that elevated plasma cortisol levels may increase the risk of endometrial cancer but not other cancers. The mechanism by which this occurs remains to be investigated.

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Fig. 1: A directed acyclic graph representing the MR framework, with the present MR study as an example.
Fig. 2: Associations of genetically predicted plasma cortisol with risk of overall and common site-specific cancers.

Data availability

All data used in this study are publicly available summary-level data, with the relevant studies cited.

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Acknowledgements

The authors would like to thank the investigators of the Breast Cancer Association Consortium (BCAC), Endometrial Cancer Association Consortium (ECAC), Genetic Investigation of ANthropometric Traits (GIANT) consortium, International Lung Cancer Consortium (ILCCO), Meta-Analyses of Glucose and Insulin-related traits consortium (MAGIC), Ovarian Cancer Association Consortium (OCAC), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium, and the FinnGen consortium for sharing summary-level GWAS data. Analyses of UK Biobank data were performed under application 29202.

Funding

SCL acknowledges research support from the Swedish Research Council (Vetenskapsrådet, 2016-01042 and 2019-00977), the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123), and the Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20190247). SK is supported by United Kingdom Research and Innovation Future Leaders Fellowship (MR/T043202/1). SB is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). During the conduction of this study, EA was supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant no. 116074 and is currently funded by the British Heart Foundation Programme Grant RG/18/13/33946. This work was supported by core funding from: the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)*. This work was also supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome. *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

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Contributions

SCL had full access to the data. SCL, SB, and EA designed the study. SCL performed the statistical analyses and created the figure. SCL, W-HL, and EA drafted the manuscript. SCL, W-HL, SK, SB, and EA interpreted the data and edited the manuscript. All authors have given final approval of the version to be published.

Corresponding author

Correspondence to Susanna C. Larsson.

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The authors declare no competing interests.

Ethics approval and consent to participate

Ethics approval and consent to participate had been obtained. The present analyses were approved by the Swedish Ethical Review Authority. The study was performed in accordance with the Declaration of Helsinki.

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Larsson, S.C., Lee, WH., Kar, S. et al. Assessing the role of cortisol in cancer: a wide-ranged Mendelian randomisation study. Br J Cancer 125, 1025–1029 (2021). https://doi.org/10.1038/s41416-021-01505-8

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