Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort

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Bonilla, C; Lewis, SJ; Martin, RM; Donovan, JL; Hamdy, FC; Neal, DE; Eeles, R; Easton, D; Kote-Jarai, Z; Al Olama, AA; ...Date
2016-04-04Source Title
BMC MedicinePublisher
BMCAffiliation
Melbourne School of Population and Global HealthClinical Pathology
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Bonilla, C., Lewis, S. J., Martin, R. M., Donovan, J. L., Hamdy, F. C., Neal, D. E., Eeles, R., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Wiklund, F., Gronberg, H., Haiman, C. A., Schleutker, J., Nordestgaard, B. G., Travis, R. C. ,... Smith, G. D. (2016). Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort. BMC MEDICINE, 14 (1), https://doi.org/10.1186/s12916-016-0602-x.Access Status
Open AccessAbstract
BACKGROUND: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. METHODS: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. RESULTS: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. CONCLUSIONS: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.
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