TY - JOUR
T1 - Circulating free testosterone and risk of aggressive prostate cancer
T2 - prospective and Mendelian randomization analyses in international consortia
AU - PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS
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, H 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
AU - Thysell, Elin
AU - Tsai, Chiaojung Jillian
AU - Tsugane, Shoichiro
AU - Vatten, Lars
AU - Weiderpass, Elisabete
AU - Weinstein, Stephanie J
AU - Wilkens, Lynne R
AU - Yeap, Bu B
AU - Allen, Naomi E
AU - Key, Timothy J
AU - Travis, Ruth C
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 1,870 aggressive prostate cancers). In Mendelian randomization (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 =0.0003: 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 1,870 aggressive prostate cancers). In Mendelian randomization (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 =0.0003: 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.
UR - http://www.scopus.com/inward/record.url?scp=85133539795&partnerID=8YFLogxK
U2 - 10.1002/ijc.34116
DO - 10.1002/ijc.34116
M3 - Article
C2 - 35579976
VL - 151
SP - 1033
EP - 1046
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 7
ER -
