title: Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort.
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.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.|MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.|MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.|National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition, Bristol, UK. richard.martin@bristol.ac.uk.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
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authors.affiliation: The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG Surrey, UK.
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mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000368:Aged; D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D011627:Puberty / Q000502:physiology; D011897:Random Allocation; D012044:Regression Analysis; D012307:Risk Factors; D012741:Sexual Maturation / Q000235:genetics*; D016019:Survival Analysis; D006113:United Kingdom / Q000453:epidemiology
keywords: Boys; Mendelian randomization; Prostate cancer; Puberty; Tanner scale