Abstract
BackgroundEpidemiological 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.MethodsWe 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.ResultsIn 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.ConclusionsOlder age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0602-x) contains supplementary material, which is available to authorized users.
Highlights
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
Circulating hormones, which rise during puberty, in particular androgens and insulin-like growth factors (IGFs), may play a role in prostate cancer initiation and progression [4, 5], the relevance of serum androgen levels has recently been called into question [6]
The IGF-I:Insulin-like growth factor binding protein (IGFBP)-3 molar ratio, an indicator of bioavailable IGF-I, was lower in patients; 30 % of men with prostate cancer were classified as having high-grade disease (Gleason score ≥7), and 12 % as having locally advanced disease (TNM stages T3-T4)
Summary
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. Circulating hormones, which rise during puberty, in particular androgens and insulin-like growth factors (IGFs), may play a role in prostate cancer initiation and progression [4, 5], the relevance of serum androgen levels has recently been called into question [6]. Age at onset of puberty may be a risk factor for prostate adenocarcinoma in men given that exposure to high levels of hormones takes place during the critical window of prostate development in adolescence [3]. Age of menarche is a well-known risk factor for breast cancer [7], but it is yet unclear whether sexual maturation influences later life cancer events in men. Timing of puberty in boys is difficult to measure as it is not defined by a specific event as in women (menarche); assessing it as a risk factor for prostate cancer in men is challenging
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