Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia

Eleanor L Watts; Aurora Perez-Cornago; Georgina K Fensom; Karl Smith-Byrne; Urwah Noor; Colm D Andrews; Marc J Gunter; Michael V Holmes; Richard M Martin; Konstantinos K Tsilidis; Demetrius Albanes; Aurelio Barricarte; Bas Bueno-de-Mesquita; Chu Chen; Barbara A Cohn; Niki L Dimou; Luigi Ferrucci; Leon Flicker; Neal D Freedman; Graham G Giles; Edward L Giovannucci; Gary E Goodman; Christopher A Haiman; Graeme J Hankey; Jiaqi Huang; Wen-Yi Huang; Lauren M Hurwitz; Rudolf Kaaks; Paul Knekt; Tatsuhiko Kubo; Hilde Langseth; Gail Laughlin; Loic Le Marchand; Tapio Luostarinen; Robert J MacInnis; Hanna O Mäenpää; Satu Männistö; E Jeffrey Metter; Kazuya Mikami; Lorelei A Mucci; Anja W Olsen; Kotaro Ozasa; Domenico Palli; Kathryn L Penney; Elizabeth A Platz; Harri Rissanen; Norie Sawada; Jeannette M Schenk; Pär Stattin; Akiko Tamakoshi; Elin Thysell; Chiaojung Jillian Tsai; Shoichiro Tsugane; Lars Vatten; Elisabete Weiderpass; Stephanie J Weinstein; Lynne R Wilkens; Bu B Yeap; PRACTICAL Consortium; CRUK; BPC3; CAPS; PEGASUS; Naomi E Allen; Timothy J Key; Ruth C Travis

doi:10.1002/ijc.34116

Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia

Int J Cancer. 2022 Oct 1;151(7):1033-1046. doi: 10.1002/ijc.34116. Epub 2022 Jun 7.

Authors

Eleanor L Watts¹, Aurora Perez-Cornago¹, Georgina K Fensom¹, Karl Smith-Byrne², Urwah Noor¹, Colm D Andrews¹, Marc J Gunter³, Michael V Holmes^{4

5}, Richard M Martin^{6

7

8}, Konstantinos K Tsilidis^{9

10}, Demetrius Albanes¹¹, Aurelio Barricarte^{12

13

14}, Bas Bueno-de-Mesquita¹⁵, Chu Chen^{16

17

18}, Barbara A Cohn¹⁹, Niki L Dimou³, Luigi Ferrucci²⁰, Leon Flicker^{21

22}, Neal D Freedman¹¹, Graham G Giles^{23

24

25}, Edward L Giovannucci^{26

27

28}, Gary E Goodman¹⁶, Christopher A Haiman²⁹, Graeme J Hankey²¹, Jiaqi Huang^{11

30}, Wen-Yi Huang¹¹, Lauren M Hurwitz¹¹, Rudolf Kaaks³¹, Paul Knekt³², Tatsuhiko Kubo³³, Hilde Langseth^{9

34}, Gail Laughlin³⁵, Loic Le Marchand³⁶, Tapio Luostarinen³⁷, Robert J MacInnis^{23

24}, Hanna O Mäenpää³⁸, Satu Männistö³⁹, E Jeffrey Metter⁴⁰, Kazuya Mikami⁴¹, Lorelei A Mucci²⁶, Anja W Olsen^{42

43}, Kotaro Ozasa⁴⁴, Domenico Palli⁴⁵, Kathryn L Penney^{26

27}, Elizabeth A Platz⁴⁶, Harri Rissanen³², Norie Sawada⁴⁷, Jeannette M Schenk⁴⁸, Pär Stattin⁴⁹, Akiko Tamakoshi⁵⁰, Elin Thysell⁵¹, Chiaojung Jillian Tsai⁵², Shoichiro Tsugane⁴⁷, Lars Vatten⁵³, Elisabete Weiderpass⁵⁴, Stephanie J Weinstein¹¹, Lynne R Wilkens³⁶, Bu B Yeap^{21

55}; PRACTICAL Consortium; CRUK; BPC3; CAPS; PEGASUS; Naomi E Allen^{4

56}, Timothy J Key¹, Ruth C Travis¹

Affiliations

¹ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
² Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
³ Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
⁴ Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK.
⁶ Department of Population Health Sciences, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁷ MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁸ National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
⁹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
¹⁰ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
¹¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹² Navarra Public Health Institute, Pamplona, Spain.
¹³ Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
¹⁴ CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain.
¹⁵ Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), The Netherlands.
¹⁶ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁷ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Otolaryngology: Head and Neck Surgery, School of Medicine, University of Washington, Seattle, Washington, USA.
¹⁹ Child Health and Development Studies, Public Health Institute, Berkeley, California, USA.
²⁰ National Institute on Aging, Baltimore, Maryland, USA.
²¹ Medical School, University of Western Australia, Perth, Western Australia, Australia.
²² Western Australian Centre for Health and Ageing, University of Western Australia, Perth, Western Australia, Australia.
²³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
²⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia.
²⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
²⁷ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
²⁸ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
²⁹ Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA.
³⁰ National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
³¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³² Department of Public Health and Welfare, National Institute for Health and Welfare, Helsinki, Finland.
³³ Department of Public Health and Health Policy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
³⁴ Department of Research, Cancer Registry of Norway, Oslo, Norway.
³⁵ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, San Diego, California, USA.
³⁶ University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
³⁷ Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.
³⁸ Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
³⁹ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
⁴⁰ Department of Neurology, The University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee, USA.
⁴¹ Departmemt of Urology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
⁴² Department of Public Health, Aarhus University, Aarhus, Denmark.
⁴³ Danish Cancer Society, Research Center, Copenhagen, Denmark.
⁴⁴ Departmemt of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan.
⁴⁵ Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
⁴⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁴⁷ Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
⁴⁸ Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁴⁹ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁵⁰ Hokkaido University Faculty of Medicine, Sapporo, Japan.
⁵¹ Department of Medical Biosciences, Umeå University, Umeå, Sweden.
⁵² Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁵³ Department of Public Health and Nursing, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁵⁴ Director Office, International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁵⁵ Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia.
⁵⁶ UK Biobank Ltd, Stockport, UK.

Abstract

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; P_het = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Keywords: Mendelian randomisation; SHBG; aggressive prostate cancer; prostate cancer; testosterone.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Humans
Male
Mendelian Randomization Analysis
Prostate
Prostatic Neoplasms* / epidemiology
Prostatic Neoplasms* / genetics
Risk Factors
Sex Hormone-Binding Globulin* / analysis
Testosterone

Substances

Biomarkers
Sex Hormone-Binding Globulin
Testosterone

Abstract

Publication types

MeSH terms

Substances

Grants and funding