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 language | English |
|---|---|
| Article number | 66 |
| Journal | BMC Medicine |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2016 |
| Externally published | Yes |
Keywords
- Boys
- Mendelian randomization
- Prostate cancer
- Puberty
- Tanner scale
Cite this
}
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 journal › Article › Research › peer-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 -