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Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.
Pubmed ID
33879453 (View this publication on the PubMed website)
Digital Object Identifier
Cancer Epidemiol Biomarkers Prev. 2021 Jul; Volume 30 (Issue 7): Pages 1336-1348
Dimou N, Mori N, Harlid S, Harbs J, Martin RM, Smith-Byrne K, Papadimitriou N, Bishop DT, Casey G, Colorado-Yohar SM, Cotterchio M, Cross AJ, Marchand LL, Lin Y, Offit K, Onland-Moret NC, Peters U, Potter JD, Rohan TE, Weiderpass E, more Gunter MJ, Murphy N
  • Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
  • Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
  • Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
  • MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, United Kingdom.
  • Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
  • Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
  • Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
  • Ontario Health (Cancer Care Ontario), Toronto, ON, Canada.
  • Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom. more
  • University of Hawaii Cancer Center, Honolulu, Hawaii.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York.
  • Office of the Director, International Agency for Research on Cancer, Lyon, France.

BACKGROUND: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses.

METHODS: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR.

RESULTS: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses.

CONCLUSIONS: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development.

IMPACT: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development.See related commentary by Hang and Shen, p. 1302.

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