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


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Authors

Bonilla, Carolina 
Lewis, Sarah J 
Martin, Richard M 
Donovan, Jenny L 
Hamdy, Freddie C 

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.

Description

Keywords

Boys, Mendelian randomization, Prostate cancer, Puberty, Tanner scale, Adolescent, Age of Onset, Aged, Case-Control Studies, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasm Staging, Odds Ratio, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Puberty, Random Allocation, Regression Analysis, Risk Factors, Sexual Maturation, Survival Analysis, United Kingdom

Journal Title

BMC Med

Conference Name

Journal ISSN

1741-7015
1741-7015

Volume Title

14

Publisher

Springer Science and Business Media LLC
Sponsorship
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
Medical Research Council (MR/N003284/1)
Medical Research Council (G0401527)
Cancer Research Uk (None)
Cancer Research Uk (None)
Medical Research Council (G0500966)
National Institute for Health Research (NIHR) (via University of Oxford) (HTA no. 96/20/99)
Cancer Research UK (A10710)
Cancer Research UK (A12014)
Cancer Research UK (A10118)
European Commission (223175)
TCC (None)
This work was supported by the World Cancer Research Fund (2011/419) and Cancer Research UK (C18281/A19169). The Integrative Epidemiology Unit (IEU) is supported by the MRC and the University of Bristol (G0600705, MC_UU_12013/19), and the Integrative Cancer Epidemiology Programme is supported by Cancer Research UK programme grant C18281/A19169. The National Institute for Health Research (NIHR) Bristol Nutrition Biomedical Research Unit is funded by the NIHR and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The ProtecT study is supported by the UK NIHR Health Technology Assessment (HTA) Programme (HTA 96/20/99; ISRCTN20141297). Funding for PRACTICAL and the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 – the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. We acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.