1. Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort.
- Author
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Bonilla, Carolina, Lewis, Sarah J., Martin, Richard M., Donovan, Jenny L., Hamdy, Freddie C., Neal, David E., Eeles, Rosalind, Easton, Doug, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G., Wiklund, Fredrik, Gronberg, Henrik, Haiman, Christopher A., Schleutker, Johanna, Nordestgaard, Børge G., Travis, Ruth C., and Pashayan, Nora
- Subjects
PUBERTY ,PROSTATE cancer risk factors ,EPIDEMIOLOGICAL research ,GENETIC polymorphisms ,ODDS ratio ,ADOLESCENCE ,AGE factors in disease ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,PROSTATE tumors ,REGRESSION analysis ,RESEARCH ,RESEARCH funding ,STATISTICAL sampling ,SURVIVAL analysis (Biometry) ,TUMOR classification ,EVALUATION research ,CASE-control method ,SEQUENCE analysis - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2016
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