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 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 Pashayan; Kay-Tee Khaw; Janet L Stanford; William J Blot; Stephen Thibodeau; Christiane Maier; Adam S Kibel; Cezary Cybulski; Lisa Cannon-Albright; Hermann Brenner; Jong Park; Radka Kaneva; Jyotsna Batra; Manuel R Teixeira; Hardev Pandha; Mark Lathrop; George Davey Smith

doi:10.1186/s12916-016-0602-x

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 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 Thibodeau, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Park, Radka Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev Pandha, Mark Lathrop, George Davey Smith

Institut for Klinisk Medicin

23 Citationer (Scopus)

36 Downloads (Pure)

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.

Originalsprog	Engelsk
Artikelnummer	66
Tidsskrift	BMC Medicine
Vol/bind	14
Sider (fra-til)	1-11
Antal sider	11
ISSN	1741-7015
DOI	https://doi.org/10.1186/s12916-016-0602-x
Status	Udgivet - 4 apr. 2016

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10.1186/s12916-016-0602-xLicens: CC BY

Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohortForlagets udgivne version, 905 KBLicens: CC BY

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Bonilla, C., Lewis, S. J., Martin, R. M., Donovan, J. L., Hamdy, F. C., Neal, D. E., Eeles, R., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Wiklund, F., Gronberg, H., Haiman, C. A., Schleutker, J., Nordestgaard, B. G., Travis, R. C., ... Davey Smith, G. (2016). Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort. BMC Medicine, 14, 1-11. [66]. https://doi.org/10.1186/s12916-016-0602-x

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 2016, 'Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort', BMC Medicine, bind 14, 66, s. 1-11. https://doi.org/10.1186/s12916-016-0602-x

@article{3843d1b6e78e479da176d4e423e2c192,

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 = "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",

author = "Carolina Bonilla and Lewis, {Sarah J} and Martin, {Richard M} and Donovan, {Jenny L} and Hamdy, {Freddie C} and Neal, {David E} and Rosalind Eeles 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 Stephen Thibodeau and Christiane Maier and Kibel, {Adam S} and Cezary Cybulski and Lisa Cannon-Albright and Hermann Brenner and Jong Park and Radka Kaneva and Jyotsna Batra and Teixeira, {Manuel R} and Hardev Pandha and Mark Lathrop and {Davey Smith}, George",

year = "2016",

month = apr,

day = "4",

doi = "10.1186/s12916-016-0602-x",

language = "English",

volume = "14",

pages = "1--11",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central Ltd.",

}

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

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 - Davey Smith, George

PY - 2016/4/4

Y1 - 2016/4/4

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 - Adolescent

KW - Age of Onset

KW - Aged

KW - Case-Control Studies

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Neoplasm Staging

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Prostatic Neoplasms

KW - Puberty

KW - Random Allocation

KW - Regression Analysis

KW - Risk Factors

KW - Sexual Maturation

KW - Survival Analysis

KW - United Kingdom

U2 - 10.1186/s12916-016-0602-x

DO - 10.1186/s12916-016-0602-x

M3 - Journal article

C2 - 27044414

SN - 1741-7015

VL - 14

SP - 1

EP - 11

JO - BMC Medicine

JF - BMC Medicine

M1 - 66

ER -

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

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