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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

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Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS PHENOME-WIDE MENDELIAN RANDOMISATION ANALYSIS OF 378,142 CASES REVEALS RISK FACTORS FOR EIGHT COMMON CANCERS

Article Open access 25 March 2024 VARIATION IN THE _SERPINA6/SERPINA1_ LOCUS ALTERS MORNING PLASMA CORTISOL, HEPATIC CORTICOSTEROID BINDING GLOBULIN EXPRESSION, GENE EXPRESSION IN PERIPHERAL

TISSUES, AND RISK OF CARDIOVASCULAR DISEASE Article Open access 20 January 2021 CONSIDERING HORMONE-SENSITIVE CANCERS AS A SINGLE DISEASE IN THE UK BIOBANK REVEALS SHARED AETIOLOGY Article

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2020;12:1191. Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet,

Stockholm, Sweden Susanna C. Larsson * Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden Susanna C. Larsson * BHF Cardiovascular Epidemiology

Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK Wei-Hsuan Lee, Stephen Burgess & Elias Allara * MRC Integrative Epidemiology Unit, Bristol

Medical School, University of Bristol, Bristol, UK Siddhartha Kar * MRC Biostatistics Unit, University of Cambridge, Cambridge, UK Stephen Burgess Authors * Susanna C. Larsson View author

publications You can also search for this author inPubMed Google Scholar * Wei-Hsuan Lee View author publications You can also search for this author inPubMed Google Scholar * Siddhartha Kar

View author publications You can also search for this author inPubMed Google Scholar * Stephen Burgess View author publications You can also search for this author inPubMed Google Scholar *

Elias Allara View author publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS COMPETING INTERESTS 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional

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THIS ARTICLE 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 Download citation * Received: 04 March 2021 * Revised: 28 June 2021 * Accepted: 19 July 2021 * Published: 27 July 2021 * Issue Date: 28 September

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