TY - JOUR
T1 - Circulating free testosterone and risk of aggressive prostate cancer
T2 - Prospective and Mendelian randomisation analyses in international consortia
AU - BPC3
AU - CAPS
AU - PEGASUS
AU - The PRACTICAL Consortium
AU - CRUK
AU - Watts, Eleanor L.
AU - Perez-Cornago, Aurora
AU - Fensom, Georgina K.
AU - Smith-Byrne, Karl
AU - Noor, Urwah
AU - Andrews, Colm D.
AU - Gunter, Marc J.
AU - Holmes, Michael V.
AU - Martin, Richard M.
AU - Tsilidis, Konstantinos K.
AU - Albanes, Demetrius
AU - Barricarte, Aurelio
AU - Bueno-de-Mesquita, Bas
AU - Chen, Chu
AU - Cohn, Barbara A.
AU - Dimou, Niki L.
AU - Ferrucci, Luigi
AU - Flicker, Leon
AU - Freedman, Neal D.
AU - Giles, Graham G.
AU - Giovannucci, Edward L.
AU - Goodman, Gary E.
AU - Haiman, Christopher A.
AU - Hankey, Graeme J.
AU - Huang, Jiaqi
AU - Huang, Wen Yi
AU - Hurwitz, Lauren M.
AU - Kaaks, Rudolf
AU - Knekt, Paul
AU - Kubo, Tatsuhiko
AU - Langseth, Hilde
AU - Laughlin, Gail
AU - Le Marchand, Loic
AU - Luostarinen, Tapio
AU - MacInnis, Robert J.
AU - Mäenpää, Hanna O.
AU - Männistö, Satu
AU - Metter, E. Jeffrey
AU - Mikami, Kazuya
AU - Mucci, Lorelei A.
AU - Olsen, Anja W.
AU - Ozasa, Kotaro
AU - Palli, Domenico
AU - Penney, Kathryn L.
AU - Platz, Elizabeth A.
AU - Rissanen, Harri
AU - Sawada, Norie
AU - Schenk, Jeannette M.
AU - Stattin, Pär
AU - Tamakoshi, Akiko
N1 - Publisher Copyright:
© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - 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; Phet =.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.
AB - 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; Phet =.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.
KW - Mendelian randomisation
KW - SHBG
KW - aggressive prostate cancer
KW - prostate cancer
KW - testosterone
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U2 - 10.1002/ijc.34116
DO - 10.1002/ijc.34116
M3 - Article
C2 - 35579976
AN - SCOPUS:85133539795
SN - 0020-7136
VL - 151
SP - 1033
EP - 1046
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 7
ER -