TY - JOUR
T1 - Pubertal development and prostate cancer risk
T2 - Mendelian randomization study in a population-based cohort
AU - The PRACTICAL Consortium
AU - Bonilla, Carolina
AU - Lewis, Sarah J.
AU - Martin, Richard M.
AU - Donovan, Jenny L.
AU - Hamdy, Freddie C.
AU - Neal, David E.
AU - Eeles, Rosalind
AU - Easton, Doug
AU - Kote-Jarai, Zsofia
AU - Al Olama, Ali Amin
AU - Benlloch, Sara
AU - Muir, Kenneth
AU - Giles, Graham G.
AU - Wiklund, Fredrik
AU - Gronberg, Henrik
AU - Haiman, Christopher A.
AU - Schleutker, Johanna
AU - Nordestgaard, Børge G.
AU - Travis, Ruth C.
AU - Pashayan, Nora
AU - Khaw, Kay Tee
AU - Stanford, Janet L.
AU - Blot, William J.
AU - Thibodeau, Stephen
AU - Maier, Christiane
AU - Kibel, Adam S.
AU - Cybulski, Cezary
AU - Cannon-Albright, Lisa
AU - Brenner, Hermann
AU - Park, Jong
AU - Kaneva, Radka
AU - Batra, Jyotsna
AU - Teixeira, Manuel R.
AU - Pandha, Hardev
AU - Lathrop, Mark
AU - Smith, George Davey
AU - Cook, Margaret
AU - Morga, Angela
AU - Lophatananon, Artitaya
AU - Fisher, Cyril
AU - Leongamornlert, Daniel
AU - Saunders, Edward J.
AU - Sawyer, Emma J.
AU - Govindasami, Koveela
AU - Tymrakiewicz, Malgorzata
AU - Guy, Michelle
AU - Livni, Naomi
AU - Wilkinson, Rosemary
AU - Jugurnauth-Little, Sara
AU - Schaid, Daniel J.
N1 - Funding Information:
The authors thank the tremendous contribution of all members of the ProtecT study research group, and especially the following, who were involved in this research (Prasad Bollina, Sue Bonnington, Lynn Bradshaw, James Catto, Debbie Cooper, Michael Davis, Liz Down, Andrew Doble, Alan Doherty, Garrett Durkan, Emma Elliott, David Gillatt, Pippa Herbert, Peter Holding, Joanne Howson, Mandy Jones, Roger Kockelbergh, Howard Kynaston, Teresa Lennon, Norma Lyons, Hing Leung, Malcolm Mason, Hilary Moody, Philip Powell, Alan Paul, Stephen Prescott, Derek Rosario, Patricia O'Sullivan, Pauline Thompson, Sarah Tidball). We thank Gemma Marsden and Luke Marsden, who processed the blood samples at the biorepository, and Rajeev Kumar, data manager. We also would like to thank the Center National de G?notypage, Evry, France, for genotyping the ProtecT samples. We also thank Stephen Burgess for his help with some of the Mendelian randomization analyses, and Theresa Redaniel for assistance with the survival analysis. The authors are grateful for the provision of the additional epidemiological data by the NHS R&D Directorate supported Prodigal study and the ProMPT (Prostate Mechanisms of Progression and Treatment) collaboration which is supported by the National Cancer Research Institute (NCRI) formed by the Department of Health, the Medical Research Council and Cancer Research UK (G0500966/75466). The Collaborative Oncological Gene-environment Study (COGS), within which the PRACTICAL consortium was assembled, would not have been possible without the contributions of the following: Per Hall (COGS), Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch, Ken Offit (CIMBA), Joe Dennis, Alison M. Dunning, Andrew Lee, Ed Dicks, Craig Luccarini, and the staff of the Centre for Genetic Epidemiology Laboratory; Javier Benitez, Anna Gonzalez-Neira, and the staff of the CNIO genotyping unit; Jacques Simard, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissi?re, Frederic Robidoux, and the staff of the McGill University and G?nome Qu?bec Innovation Centre; Stig E. Bojesen, Sune F. Nielsen, Maren Weischer, B?rge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory; and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer, and the staff of the Mayo Clinic Genotyping Core Facility. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation or preparation, review, or approval of the article. 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.
Publisher Copyright:
© 2016 Bonilla et al.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Boys
KW - Mendelian randomization
KW - Prostate cancer
KW - Puberty
KW - Tanner scale
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U2 - 10.1186/s12916-016-0602-x
DO - 10.1186/s12916-016-0602-x
M3 - Article
C2 - 27044414
AN - SCOPUS:85007425384
VL - 14
JO - BMC Medicine
JF - BMC Medicine
SN - 1741-7015
IS - 1
M1 - 66
ER -