Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis.

Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer.

Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium.

In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I.

These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

International journal of epidemiology. 2022 Jun 21 [Epub ahead of print]

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, H Bas Bueno-de-Mesquita, Barbara A Cohn, Melanie Deschasaux-Tanguy, Niki L Dimou, Luigi Ferrucci, Leon Flicker, Neal D Freedman, Graham G Giles, Edward L Giovannucci, Christopher A Haiman, Graham J Hankey, Jeffrey M P Holly, Jiaqi Huang, Wen-Yi Huang, Lauren M Hurwitz, Rudolf Kaaks, Tatsuhiko Kubo, Loic Le Marchand, Robert J MacInnis, Satu Männistö, E Jeffrey Metter, Kazuya Mikami, Lorelei A Mucci, Anja W Olsen, Kotaro Ozasa, Domenico Palli, Kathryn L Penney, Elizabeth A Platz, Michael N Pollak, Monique J Roobol, Catherine A Schaefer, Jeannette M Schenk, Pär Stattin, Akiko Tamakoshi, Elin Thysell, Chiaojung Jillian Tsai, Mathilde Touvier, Stephen K Van Den Eeden, 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

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK., Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France., Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France., Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK., Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Group of Epidemiology of Cancer and Other Chronic Diseases, Navarra Public Health Institute, Pamplona, Spain., Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Utrecht, The Netherlands., Child Health and Development Studies, Public Health Institute, Berkeley, CA, USA., Sorbonne Paris Nord University, Nutritional Epidemiology Research Team, Epidemiology and Statistics Research Center, University of Paris, Bobigny, France., National Institute on Aging, Baltimore, MD, USA., WA Centre for Health & Ageing, Medical School, University of Western Australia, Perth, WA, Australia., Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Department of Preventive Medicine, Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA., IGFs & Metabolic Endocrinology Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany., Department of Public Health and Health Policy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan., University of Hawaii, Cancer Center, Honolulu, HI, USA., Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia., Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland., Department of Neurology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA., Departmemt of Urology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan., Department of Public Health, Aarhus University, Aarhus, Denmark., Departmemt of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan., Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network, Florence, Italy., Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Departments of Medicine and Oncology, McGill University, Montreal, QC, Canada., Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands., Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA., Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Surgical Sciences, Uppsala University, Uppsala, Sweden., Department of Public Health, Faculty of Medicine, Hokkaido University, Sapporo, Japan., Department of Medical Biosciences, Umeå University, Umeå, Sweden., Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Director's Office, International Agency for Research on Cancer, World Health Organization, Lyon, France.

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