Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort.
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Date
2016-04-04Author
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
PRACTICAL consortium,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
PRACTICAL consortium
Humans
Prostatic Neoplasms
Neoplasm Staging
Odds Ratio
Risk Factors
Regression Analysis
Survival Analysis
Case-Control Studies
Random Allocation
Age of Onset
Puberty
Sexual Maturation
Polymorphism, Single Nucleotide
Adolescent
Aged
Middle Aged
Male
Genome-Wide Association Study
Mendelian Randomization Analysis
United Kingdom
Research team
Oncogenetics
Language
eng
Date accepted
2016-03-16
License start date
2016-04-04
Citation
BMC medicine, 2016, 14 pp. 66 - ?
Publisher
BMC