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

VL - 360

JO - The BMJ

JF - The BMJ

SN - 0959-8146

M1 - j5757

ER -