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

BMC Med. 2016 Apr 4;14:66. doi: 10.1186/s12916-016-0602-x.

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.

Keywords: Boys; Mendelian randomization; Prostate cancer; Puberty; Tanner scale.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Age of Onset
  • Aged
  • Case-Control Studies
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mendelian Randomization Analysis / methods
  • Middle Aged
  • Neoplasm Staging
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms* / epidemiology
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / pathology
  • Prostatic Neoplasms* / physiopathology
  • Puberty / physiology
  • Random Allocation
  • Regression Analysis
  • Risk Factors
  • Sexual Maturation / genetics*
  • Survival Analysis
  • United Kingdom / epidemiology