Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts

Tyler M Seibert; Chun Chieh Fan; Yunpeng Wang; Verena Zuber; Roshan Karunamuni; J Kellogg Parsons; Rosalind A Eeles; Douglas F Easton; ZSofia Kote-Jarai; Ali Amin Al Olama; Sara Benlloch Garcia; Kenneth Muir; Henrik Grönberg; Fredrik Wiklund; Markus Aly; Johanna Schleutker; Csilla Sipeky; Teuvo Lj Tammela; Børge G Nordestgaard; Sune F Nielsen; Maren Weischer; Rasmus Bisbjerg; M Andreas Røder; Peter Iversen; Tim J Key; Ruth C Travis; David E Neal; Jenny L Donovan; Freddie C Hamdy; Paul Pharoah; Nora Pashayan; Kay-Tee Khaw; Christiane Maier; Walther Vogel; Manuel Luedeke; Kathleen Herkommer; Adam S Kibel; Cezary Cybulski; Dominika Wokolorczyk; Wojciech Kluzniak; Lisa Cannon-Albright; Hermann Brenner; Katarina Cuk; Kai-Uwe Saum; Jong Y Park; Thomas A Sellers; Chavdar Slavov; Radka Kaneva; Vanio Mitev; Jyotsna Batra; PRACTICAL Consortium*

doi:10.1136/bmj.j5757

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts

Tyler M Seibert, Chun Chieh Fan, Yunpeng Wang, Verena Zuber, Roshan Karunamuni, J Kellogg Parsons, Rosalind A Eeles, Douglas F Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch Garcia, Kenneth Muir, Henrik Grönberg, Fredrik Wiklund, Markus Aly, Johanna Schleutker, Csilla Sipeky, Teuvo Lj Tammela, Børge G Nordestgaard, Sune F NielsenMaren Weischer, Rasmus Bisbjerg, M Andreas Røder, Peter Iversen, Tim J Key, Ruth C Travis, David E Neal, Jenny L Donovan, Freddie C Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Hermann Brenner, Katarina Cuk, Kai-Uwe Saum, Jong Y Park, Thomas A Sellers, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, PRACTICAL Consortium*

Department of Clinical Medicine

62 Citations (Scopus)

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Abstract

Objectives To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Main outcome measures Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10^-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

Original language	English
Article number	j5757
Journal	B M J
Volume	360
Number of pages	7
ISSN	0959-8146
DOIs	https://doi.org/10.1136/bmj.j5757
Publication status	Published - 2018

Keywords

Age of Onset
Aged
Cohort Studies
Disease-Free Survival
Early Detection of Cancer/methods
European Continental Ancestry Group/genetics
Genotype
Humans
Kallikreins/analysis
Male
Middle Aged
Outcome Assessment (Health Care)
Polymorphism, Single Nucleotide/genetics
Predictive Value of Tests
Prostate-Specific Antigen/analysis
Prostatic Neoplasms/blood
Risk Assessment
Survival Analysis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Polygenic hazard score to guide screening for aggressive prostate cancerFinal published version, 473 KBLicence: CC BY-NC

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Seibert, T. M., Fan, C. C., Wang, Y., Zuber, V., Karunamuni, R., Parsons, J. K., Eeles, R. A., Easton, D. F., Kote-Jarai, ZS., Al Olama, A. A., Garcia, S. B., Muir, K., Grönberg, H., Wiklund, F., Aly, M., Schleutker, J., Sipeky, C., Tammela, T. L., Nordestgaard, B. G., ... PRACTICAL Consortium* (2018). Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts. B M J, 360, [j5757]. https://doi.org/10.1136/bmj.j5757

Seibert, TM, Fan, CC, Wang, Y, Zuber, V, Karunamuni, R, Parsons, JK, Eeles, RA, Easton, DF, Kote-Jarai, ZS, Al Olama, AA, Garcia, SB, Muir, K, Grönberg, H, Wiklund, F, Aly, M, Schleutker, J, Sipeky, C, Tammela, TL, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bisbjerg, R, Røder, MA, Iversen, P, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, K-T, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Brenner, H, Cuk, K, Saum, K-U, Park, JY, Sellers, TA, Slavov, C, Kaneva, R, Mitev, V, Batra, J & PRACTICAL Consortium* 2018, 'Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts', B M J, vol. 360, j5757. https://doi.org/10.1136/bmj.j5757

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title = "Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts",

abstract = "Objectives To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Main outcome measures Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.",

keywords = "Age of Onset, Aged, Cohort Studies, Disease-Free Survival, Early Detection of Cancer/methods, European Continental Ancestry Group/genetics, Genotype, Humans, Kallikreins/analysis, Male, Middle Aged, Outcome Assessment (Health Care), Polymorphism, Single Nucleotide/genetics, Predictive Value of Tests, Prostate-Specific Antigen/analysis, Prostatic Neoplasms/blood, Risk Assessment, Survival Analysis",

author = "Seibert, {Tyler M} and Fan, {Chun Chieh} and Yunpeng Wang and Verena Zuber and Roshan Karunamuni and Parsons, {J Kellogg} and Eeles, {Rosalind A} and Easton, {Douglas F} and ZSofia Kote-Jarai and {Al Olama}, {Ali Amin} and Garcia, {Sara Benlloch} and Kenneth Muir and Henrik Gr{\"o}nberg and Fredrik Wiklund and Markus Aly and Johanna Schleutker and Csilla Sipeky and Tammela, {Teuvo Lj} and Nordestgaard, {B{\o}rge G} and Nielsen, {Sune F} and Maren Weischer and Rasmus Bisbjerg and R{\o}der, {M Andreas} and Peter Iversen and Key, {Tim J} and Travis, {Ruth C} and Neal, {David E} and Donovan, {Jenny L} and Hamdy, {Freddie C} and Paul Pharoah and Nora Pashayan and Kay-Tee Khaw and Christiane Maier and Walther Vogel and Manuel Luedeke and Kathleen Herkommer and Kibel, {Adam S} and Cezary Cybulski and Dominika Wokolorczyk and Wojciech Kluzniak and Lisa Cannon-Albright and Hermann Brenner and Katarina Cuk and Kai-Uwe Saum and Park, {Jong Y} and Sellers, {Thomas A} and Chavdar Slavov and Radka Kaneva and Vanio Mitev and Jyotsna Batra and {PRACTICAL Consortium*}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2018",

doi = "10.1136/bmj.j5757",

language = "English",

volume = "360",

journal = "The BMJ",

issn = "0959-8146",

publisher = "BMJ Publishing Group",

}

TY - JOUR

T1 - Polygenic hazard score to guide screening for aggressive prostate cancer

T2 - development and validation in large scale cohorts

AU - Seibert, Tyler M

AU - Fan, Chun Chieh

AU - Wang, Yunpeng

AU - Zuber, Verena

AU - Karunamuni, Roshan

AU - Parsons, J Kellogg

AU - Eeles, Rosalind A

AU - Easton, Douglas F

AU - Kote-Jarai, ZSofia

AU - Al Olama, Ali Amin

AU - Garcia, Sara Benlloch

AU - Muir, Kenneth

AU - Grönberg, Henrik

AU - Wiklund, Fredrik

AU - Aly, Markus

AU - Schleutker, Johanna

AU - Sipeky, Csilla

AU - Tammela, Teuvo Lj

AU - Nordestgaard, Børge G

AU - Nielsen, Sune F

AU - Weischer, Maren

AU - Bisbjerg, Rasmus

AU - Røder, M Andreas

AU - Iversen, Peter

AU - Key, Tim J

AU - Travis, Ruth C

AU - Neal, David E

AU - Donovan, Jenny L

AU - Hamdy, Freddie C

AU - Pharoah, Paul

AU - Pashayan, Nora

AU - Khaw, Kay-Tee

AU - Maier, Christiane

AU - Vogel, Walther

AU - Luedeke, Manuel

AU - Herkommer, Kathleen

AU - Kibel, Adam S

AU - Cybulski, Cezary

AU - Wokolorczyk, Dominika

AU - Kluzniak, Wojciech

AU - Cannon-Albright, Lisa

AU - Brenner, Hermann

AU - Cuk, Katarina

AU - Saum, Kai-Uwe

AU - Park, Jong Y

AU - Sellers, Thomas A

AU - Slavov, Chavdar

AU - Kaneva, Radka

AU - Mitev, Vanio

AU - Batra, Jyotsna

AU - PRACTICAL Consortium

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2018

Y1 - 2018

N2 - Objectives To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Main outcome measures Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

AB - Objectives To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Design Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Main outcome measures Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

KW - Age of Onset

KW - Aged

KW - Cohort Studies

KW - Disease-Free Survival

KW - Early Detection of Cancer/methods

KW - European Continental Ancestry Group/genetics

KW - Genotype

KW - Humans

KW - Kallikreins/analysis

KW - Male

KW - Middle Aged

KW - Outcome Assessment (Health Care)

KW - Polymorphism, Single Nucleotide/genetics

KW - Predictive Value of Tests

KW - Prostate-Specific Antigen/analysis

KW - Prostatic Neoplasms/blood

KW - Risk Assessment

KW - Survival Analysis

U2 - 10.1136/bmj.j5757

DO - 10.1136/bmj.j5757

M3 - Journal article

C2 - 29321194

SN - 0959-8146

VL - 360

JO - The BMJ

JF - The BMJ

M1 - j5757

ER -

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts

Abstract

Keywords

UN SDGs

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