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

Carolina Bonilla, Sarah J. Lewis, Richard M Martin, Jenny L. Donovan, Freddie C Hamdy, David E. Neal, Rosalind A Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A Haiman, Johanna Schleutker, Børge G. Nordestgaard, Ruth C Travis, Nora PashayanKay-Tee Khaw, Janet L. Stanford, William J. Blot, Stephen N. Thibodeau, Christiane Maier, Adam S. Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Hyuk Park, Radka P. Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev S Pandha, Mark G Lathrop, George Davey Smith, Margaret Cook, Angela Morga, Artitaya Lophatananon, Cyril Fisher, Daniel Leongamornlert, Edward J. Saunders, Emma J. Sawyer, Koveela Govindasami, Malgorzata Tymrakiewicz, Michelle Guy, Naomi Livni, Rosemary A Wilkinson, Sara Jugurnauth-Little, Steve Hazel, Tokhir Dadaev, Melissa C. Southey, Liesel M. Fitzgerald, John Pedersen, John Hopper, Ami Karlsson, Carin Cavalli-Bjoerkman, Jan Erik Johansson, Jan Adolfson, Markus Aly, Michael Broms, Paer Stattin, Brian E Henderson, Fredrick Schumacher, Anssi Auvinen, Kimmo Taari, Liisa Maeaettaenen, Paula Kujala, Teemu Murtola, Teuvo L.J. Tammela, Csilla Sipeky, Martin Andreas Roder, Peter Iversen, Peter Klarskov, Sune F Nielsen, Maren Weischer, Tim J. Key, Hans Wallinder, Sven Gustafsson, Angela Cox, Anne George, Athene Lane, Gemma Marsden, Michael Davis, Paul Brown, Paul D P Pharoah, Lisa B. Signorello, Wei Zheng, Shannon K. McDonnell, Daniel J. Schaid, Liang Wang, Lori Tillmans, Shaun Riska, Thomas Schnoeller, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Dominika Wokozorczyk, Jan Lubiski, Wojciech Kluzniak, Katja Butterbach, Christa Stegmaier, Bernd Holleczek, Babu Zachariah, Hui Yi Lim, Hyun Park, James Haley, Julio M. Pow-Sang, Maria Rincon, Selina Radlein, Thomas A Sellers, Chavdar Slavov, Aleksandrina Vlahova, Atanaska Mitkova, Darina Kachakova, Elenko Popov, Svetlana Christova, Tihomir Dikov, Vanio Mitev, Allison Eckert, Angus Collins, Glenn Wood, Greg Malone, Judith A. Clements, Kris M Kerr, Megan Turner, Pamela Saunders, Peter Heathcote, Gail Risbridger, Wayne Tilley, Lisa Horvath, Trina Yeadon, Srilakshmi Srinivasan, Leire Moya, Amanda B Spurdle, Joana M Santos, Carmen Jerónimo, Paula Paulo, Pedro Telles Cougo-Pinto, Rui Henrique, Sofia Maia, Agnieszka Michael, Andrzej Kierzek, Huihai Wu, The PRACTICAL consortium

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Article number66
JournalBMC Medicine
Volume14
Issue number1
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Boys
  • Mendelian randomization
  • Prostate cancer
  • Puberty
  • Tanner scale

Cite this

Bonilla, C., Lewis, S. J., Martin, R. M., Donovan, J. L., Hamdy, F. C., Neal, D. E., ... The PRACTICAL consortium (2016). Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort. BMC Medicine, 14(1), [66]. https://doi.org/10.1186/s12916-016-0602-x
Bonilla, Carolina ; Lewis, Sarah J. ; Martin, Richard M ; Donovan, Jenny L. ; Hamdy, Freddie C ; Neal, David E. ; Eeles, Rosalind A ; Easton, Doug ; Kote-Jarai, Zsofia ; Al Olama, Ali Amin ; Benlloch, Sara ; Muir, Kenneth ; Giles, Graham G. ; Wiklund, Fredrik ; Gronberg, Henrik ; Haiman, Christopher A ; Schleutker, Johanna ; Nordestgaard, Børge G. ; Travis, Ruth C ; Pashayan, Nora ; Khaw, Kay-Tee ; Stanford, Janet L. ; Blot, William J. ; Thibodeau, Stephen N. ; Maier, Christiane ; Kibel, Adam S. ; Cybulski, Cezary ; Cannon-Albright, Lisa ; Brenner, Hermann ; Park, Jong Hyuk ; Kaneva, Radka P. ; Batra, Jyotsna ; Teixeira, Manuel R ; Pandha, Hardev S ; Lathrop, Mark G ; Smith, George Davey ; Cook, Margaret ; Morga, Angela ; Lophatananon, Artitaya ; Fisher, Cyril ; Leongamornlert, Daniel ; Saunders, Edward J. ; Sawyer, Emma J. ; Govindasami, Koveela ; Tymrakiewicz, Malgorzata ; Guy, Michelle ; Livni, Naomi ; Wilkinson, Rosemary A ; Jugurnauth-Little, Sara ; Hazel, Steve ; Dadaev, Tokhir ; Southey, Melissa C. ; Fitzgerald, Liesel M. ; Pedersen, John ; Hopper, John ; Karlsson, Ami ; Cavalli-Bjoerkman, Carin ; Johansson, Jan Erik ; Adolfson, Jan ; Aly, Markus ; Broms, Michael ; Stattin, Paer ; Henderson, Brian E ; Schumacher, Fredrick ; Auvinen, Anssi ; Taari, Kimmo ; Maeaettaenen, Liisa ; Kujala, Paula ; Murtola, Teemu ; Tammela, Teuvo L.J. ; Sipeky, Csilla ; Roder, Martin Andreas ; Iversen, Peter ; Klarskov, Peter ; Nielsen, Sune F ; Weischer, Maren ; Key, Tim J. ; Wallinder, Hans ; Gustafsson, Sven ; Cox, Angela ; George, Anne ; Lane, Athene ; Marsden, Gemma ; Davis, Michael ; Brown, Paul ; Pharoah, Paul D P ; Signorello, Lisa B. ; Zheng, Wei ; McDonnell, Shannon K. ; Schaid, Daniel J. ; Wang, Liang ; Tillmans, Lori ; Riska, Shaun ; Schnoeller, Thomas ; Herkommer, Kathleen ; Luedeke, Manuel ; Vogel, Walther ; Wokozorczyk, Dominika ; Lubiski, Jan ; Kluzniak, Wojciech ; Butterbach, Katja ; Stegmaier, Christa ; Holleczek, Bernd ; Zachariah, Babu ; Lim, Hui Yi ; Park, Hyun ; Haley, James ; Pow-Sang, Julio M. ; Rincon, Maria ; Radlein, Selina ; Sellers, Thomas A ; Slavov, Chavdar ; Vlahova, Aleksandrina ; Mitkova, Atanaska ; Kachakova, Darina ; Popov, Elenko ; Christova, Svetlana ; Dikov, Tihomir ; Mitev, Vanio ; Eckert, Allison ; Collins, Angus ; Wood, Glenn ; Malone, Greg ; Clements, Judith A. ; Kerr, Kris M ; Turner, Megan ; Saunders, Pamela ; Heathcote, Peter ; Risbridger, Gail ; Tilley, Wayne ; Horvath, Lisa ; Yeadon, Trina ; Srinivasan, Srilakshmi ; Moya, Leire ; Spurdle, Amanda B ; Santos, Joana M ; Jerónimo, Carmen ; Paulo, Paula ; Cougo-Pinto, Pedro Telles ; Henrique, Rui ; Maia, Sofia ; Michael, Agnieszka ; Kierzek, Andrzej ; Wu, Huihai ; The PRACTICAL consortium. / Pubertal development and prostate cancer risk : Mendelian randomization study in a population-based cohort. In: BMC Medicine. 2016 ; Vol. 14, No. 1.
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title = "Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort",
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",
author = "Carolina Bonilla and Lewis, {Sarah J.} and Martin, {Richard M} and Donovan, {Jenny L.} and Hamdy, {Freddie C} and Neal, {David E.} and Eeles, {Rosalind A} and Doug Easton and Zsofia Kote-Jarai and {Al Olama}, {Ali Amin} and Sara Benlloch and Kenneth Muir and Giles, {Graham G.} and Fredrik Wiklund and Henrik Gronberg and Haiman, {Christopher A} and Johanna Schleutker and Nordestgaard, {B{\o}rge G.} and Travis, {Ruth C} and Nora Pashayan and Kay-Tee Khaw and Stanford, {Janet L.} and Blot, {William J.} and Thibodeau, {Stephen N.} and Christiane Maier and Kibel, {Adam S.} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Park, {Jong Hyuk} and Kaneva, {Radka P.} and Jyotsna Batra and Teixeira, {Manuel R} and Pandha, {Hardev S} and Lathrop, {Mark G} and Smith, {George Davey} and Margaret Cook and Angela Morga and Artitaya Lophatananon and Cyril Fisher and Daniel Leongamornlert and Saunders, {Edward J.} and Sawyer, {Emma J.} and Koveela Govindasami and Malgorzata Tymrakiewicz and Michelle Guy and Naomi Livni and Wilkinson, {Rosemary A} and Sara Jugurnauth-Little and Steve Hazel and Tokhir Dadaev and Southey, {Melissa C.} and Fitzgerald, {Liesel M.} and John Pedersen and John Hopper and Ami Karlsson and Carin Cavalli-Bjoerkman and Johansson, {Jan Erik} and Jan Adolfson and Markus Aly and Michael Broms and Paer Stattin and Henderson, {Brian E} and Fredrick Schumacher and Anssi Auvinen and Kimmo Taari and Liisa Maeaettaenen and Paula Kujala and Teemu Murtola and Tammela, {Teuvo L.J.} and Csilla Sipeky and Roder, {Martin Andreas} and Peter Iversen and Peter Klarskov and Nielsen, {Sune F} and Maren Weischer and Key, {Tim J.} and Hans Wallinder and Sven Gustafsson and Angela Cox and Anne George and Athene Lane and Gemma Marsden and Michael Davis and Paul Brown and Pharoah, {Paul D P} and Signorello, {Lisa B.} and Wei Zheng and McDonnell, {Shannon K.} and Schaid, {Daniel J.} and Liang Wang and Lori Tillmans and Shaun Riska and Thomas Schnoeller and Kathleen Herkommer and Manuel Luedeke and Walther Vogel and Dominika Wokozorczyk and Jan Lubiski and Wojciech Kluzniak and Katja Butterbach and Christa Stegmaier and Bernd Holleczek and Babu Zachariah and Lim, {Hui Yi} and Hyun Park and James Haley and Pow-Sang, {Julio M.} and Maria Rincon and Selina Radlein and Sellers, {Thomas A} and Chavdar Slavov and Aleksandrina Vlahova and Atanaska Mitkova and Darina Kachakova and Elenko Popov and Svetlana Christova and Tihomir Dikov and Vanio Mitev and Allison Eckert and Angus Collins and Glenn Wood and Greg Malone and Clements, {Judith A.} and Kerr, {Kris M} and Megan Turner and Pamela Saunders and Peter Heathcote and Gail Risbridger and Wayne Tilley and Lisa Horvath and Trina Yeadon and Srilakshmi Srinivasan and Leire Moya and Spurdle, {Amanda B} and Santos, {Joana M} and Carmen Jer{\'o}nimo and Paula Paulo and Cougo-Pinto, {Pedro Telles} and Rui Henrique and Sofia Maia and Agnieszka Michael and Andrzej Kierzek and Huihai Wu and {The PRACTICAL consortium}",
year = "2016",
doi = "10.1186/s12916-016-0602-x",
language = "English",
volume = "14",
journal = "BMC Medicine",
issn = "1741-7015",
publisher = "Springer-Verlag London Ltd.",
number = "1",

}

Bonilla, C, Lewis, SJ, Martin, RM, Donovan, JL, Hamdy, FC, Neal, DE, Eeles, RA, 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, SN, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, JH, Kaneva, RP, Batra, J, Teixeira, MR, Pandha, HS, Lathrop, MG, Smith, GD, Cook, M, Morga, A, Lophatananon, A, Fisher, C, Leongamornlert, D, Saunders, EJ, Sawyer, EJ, Govindasami, K, Tymrakiewicz, M, Guy, M, Livni, N, Wilkinson, RA, Jugurnauth-Little, S, Hazel, S, Dadaev, T, Southey, MC, Fitzgerald, LM, Pedersen, J, Hopper, J, Karlsson, A, Cavalli-Bjoerkman, C, Johansson, JE, Adolfson, J, Aly, M, Broms, M, Stattin, P, Henderson, BE, Schumacher, F, Auvinen, A, Taari, K, Maeaettaenen, L, Kujala, P, Murtola, T, Tammela, TLJ, Sipeky, C, Roder, MA, Iversen, P, Klarskov, P, Nielsen, SF, Weischer, M, Key, TJ, Wallinder, H, Gustafsson, S, Cox, A, George, A, Lane, A, Marsden, G, Davis, M, Brown, P, Pharoah, PDP, Signorello, LB, Zheng, W, McDonnell, SK, Schaid, DJ, Wang, L, Tillmans, L, Riska, S, Schnoeller, T, Herkommer, K, Luedeke, M, Vogel, W, Wokozorczyk, D, Lubiski, J, Kluzniak, W, Butterbach, K, Stegmaier, C, Holleczek, B, Zachariah, B, Lim, HY, Park, H, Haley, J, Pow-Sang, JM, Rincon, M, Radlein, S, Sellers, TA, Slavov, C, Vlahova, A, Mitkova, A, Kachakova, D, Popov, E, Christova, S, Dikov, T, Mitev, V, Eckert, A, Collins, A, Wood, G, Malone, G, Clements, JA, Kerr, KM, Turner, M, Saunders, P, Heathcote, P, Risbridger, G, Tilley, W, Horvath, L, Yeadon, T, Srinivasan, S, Moya, L, Spurdle, AB, Santos, JM, Jerónimo, C, Paulo, P, Cougo-Pinto, PT, Henrique, R, Maia, S, Michael, A, Kierzek, A, Wu, H & The PRACTICAL consortium 2016, 'Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort', BMC Medicine, vol. 14, no. 1, 66. https://doi.org/10.1186/s12916-016-0602-x

Pubertal development and prostate cancer risk : Mendelian randomization study in a population-based cohort. / Bonilla, Carolina; Lewis, Sarah J.; Martin, Richard M; Donovan, Jenny L.; Hamdy, Freddie C; Neal, David E.; Eeles, Rosalind A; Easton, Doug; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Børge G.; Travis, Ruth C; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Blot, William J.; Thibodeau, Stephen N.; Maier, Christiane; Kibel, Adam S.; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong Hyuk; Kaneva, Radka P.; Batra, Jyotsna; Teixeira, Manuel R; Pandha, Hardev S; Lathrop, Mark G; Smith, George Davey; Cook, Margaret; Morga, Angela; Lophatananon, Artitaya; Fisher, Cyril; Leongamornlert, Daniel; Saunders, Edward J.; Sawyer, Emma J.; Govindasami, Koveela; Tymrakiewicz, Malgorzata; Guy, Michelle; Livni, Naomi; Wilkinson, Rosemary A; Jugurnauth-Little, Sara; Hazel, Steve; Dadaev, Tokhir; Southey, Melissa C.; Fitzgerald, Liesel M.; Pedersen, John; Hopper, John; Karlsson, Ami; Cavalli-Bjoerkman, Carin; Johansson, Jan Erik; Adolfson, Jan; Aly, Markus; Broms, Michael; Stattin, Paer; Henderson, Brian E; Schumacher, Fredrick; Auvinen, Anssi; Taari, Kimmo; Maeaettaenen, Liisa; Kujala, Paula; Murtola, Teemu; Tammela, Teuvo L.J.; Sipeky, Csilla; Roder, Martin Andreas; Iversen, Peter; Klarskov, Peter; Nielsen, Sune F; Weischer, Maren; Key, Tim J.; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; George, Anne; Lane, Athene; Marsden, Gemma; Davis, Michael; Brown, Paul; Pharoah, Paul D P; Signorello, Lisa B.; Zheng, Wei; McDonnell, Shannon K.; Schaid, Daniel J.; Wang, Liang; Tillmans, Lori; Riska, Shaun; Schnoeller, Thomas; Herkommer, Kathleen; Luedeke, Manuel; Vogel, Walther; Wokozorczyk, Dominika; Lubiski, Jan; Kluzniak, Wojciech; Butterbach, Katja; Stegmaier, Christa; Holleczek, Bernd; Zachariah, Babu; Lim, Hui Yi; Park, Hyun; Haley, James; Pow-Sang, Julio M.; Rincon, Maria; Radlein, Selina; Sellers, Thomas A; Slavov, Chavdar; Vlahova, Aleksandrina; Mitkova, Atanaska; Kachakova, Darina; Popov, Elenko; Christova, Svetlana; Dikov, Tihomir; Mitev, Vanio; Eckert, Allison; Collins, Angus; Wood, Glenn; Malone, Greg; Clements, Judith A.; Kerr, Kris M; Turner, Megan; Saunders, Pamela; Heathcote, Peter; Risbridger, Gail; Tilley, Wayne; Horvath, Lisa; Yeadon, Trina; Srinivasan, Srilakshmi; Moya, Leire; Spurdle, Amanda B; Santos, Joana M; Jerónimo, Carmen; Paulo, Paula; Cougo-Pinto, Pedro Telles; Henrique, Rui; Maia, Sofia; Michael, Agnieszka; Kierzek, Andrzej; Wu, Huihai; The PRACTICAL consortium.

In: BMC Medicine, Vol. 14, No. 1, 66, 2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pubertal development and prostate cancer risk

T2 - Mendelian randomization study in a population-based cohort

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 A

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 N.

AU - Maier, Christiane

AU - Kibel, Adam S.

AU - Cybulski, Cezary

AU - Cannon-Albright, Lisa

AU - Brenner, Hermann

AU - Park, Jong Hyuk

AU - Kaneva, Radka P.

AU - Batra, Jyotsna

AU - Teixeira, Manuel R

AU - Pandha, Hardev S

AU - Lathrop, Mark G

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 A

AU - Jugurnauth-Little, Sara

AU - Hazel, Steve

AU - Dadaev, Tokhir

AU - Southey, Melissa C.

AU - Fitzgerald, Liesel M.

AU - Pedersen, John

AU - Hopper, John

AU - Karlsson, Ami

AU - Cavalli-Bjoerkman, Carin

AU - Johansson, Jan Erik

AU - Adolfson, Jan

AU - Aly, Markus

AU - Broms, Michael

AU - Stattin, Paer

AU - Henderson, Brian E

AU - Schumacher, Fredrick

AU - Auvinen, Anssi

AU - Taari, Kimmo

AU - Maeaettaenen, Liisa

AU - Kujala, Paula

AU - Murtola, Teemu

AU - Tammela, Teuvo L.J.

AU - Sipeky, Csilla

AU - Roder, Martin Andreas

AU - Iversen, Peter

AU - Klarskov, Peter

AU - Nielsen, Sune F

AU - Weischer, Maren

AU - Key, Tim J.

AU - Wallinder, Hans

AU - Gustafsson, Sven

AU - Cox, Angela

AU - George, Anne

AU - Lane, Athene

AU - Marsden, Gemma

AU - Davis, Michael

AU - Brown, Paul

AU - Pharoah, Paul D P

AU - Signorello, Lisa B.

AU - Zheng, Wei

AU - McDonnell, Shannon K.

AU - Schaid, Daniel J.

AU - Wang, Liang

AU - Tillmans, Lori

AU - Riska, Shaun

AU - Schnoeller, Thomas

AU - Herkommer, Kathleen

AU - Luedeke, Manuel

AU - Vogel, Walther

AU - Wokozorczyk, Dominika

AU - Lubiski, Jan

AU - Kluzniak, Wojciech

AU - Butterbach, Katja

AU - Stegmaier, Christa

AU - Holleczek, Bernd

AU - Zachariah, Babu

AU - Lim, Hui Yi

AU - Park, Hyun

AU - Haley, James

AU - Pow-Sang, Julio M.

AU - Rincon, Maria

AU - Radlein, Selina

AU - Sellers, Thomas A

AU - Slavov, Chavdar

AU - Vlahova, Aleksandrina

AU - Mitkova, Atanaska

AU - Kachakova, Darina

AU - Popov, Elenko

AU - Christova, Svetlana

AU - Dikov, Tihomir

AU - Mitev, Vanio

AU - Eckert, Allison

AU - Collins, Angus

AU - Wood, Glenn

AU - Malone, Greg

AU - Clements, Judith A.

AU - Kerr, Kris M

AU - Turner, Megan

AU - Saunders, Pamela

AU - Heathcote, Peter

AU - Risbridger, Gail

AU - Tilley, Wayne

AU - Horvath, Lisa

AU - Yeadon, Trina

AU - Srinivasan, Srilakshmi

AU - Moya, Leire

AU - Spurdle, Amanda B

AU - Santos, Joana M

AU - Jerónimo, Carmen

AU - Paulo, Paula

AU - Cougo-Pinto, Pedro Telles

AU - Henrique, Rui

AU - Maia, Sofia

AU - Michael, Agnieszka

AU - Kierzek, Andrzej

AU - Wu, Huihai

AU - The PRACTICAL consortium

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

UR - http://www.scopus.com/inward/record.url?scp=85007425384&partnerID=8YFLogxK

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 -