Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort.
Bonilla C., Lewis SJ., Martin RM., Donovan JL., Hamdy FC., Neal DE., Eeles R., Easton D., Kote-Jarai Z., Al Olama AA., Benlloch S., Muir K., Giles GG., Wiklund F., Gronberg H., Haiman CA., Schleutker J., Nordestgaard BG., Travis RC., Pashayan N., Khaw K-T., Stanford JL., Blot WJ., Thibodeau S., Maier C., Kibel AS., Cybulski C., Cannon-Albright L., Brenner H., Park J., Kaneva R., Batra J., Teixeira MR., Pandha H., Lathrop M., Davey Smith G.
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.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.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.Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.