A1 Refereed original research article in a scientific journal
Polygenic hazard score to guide screening for aggressive - prostate cancer: development and validation in large scale - cohorts
Authors: 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, Judith A Clements, Amanda Spurdle,
Manuel R Teixeira, Paula Paulo, Sofia Maia, Hardev Pandha, Agnieszka Michael,
Andrzej Kierzek, David S Karow, Ian G Mills, Ole A Andreassen, Anders M Dale,
The PRACTICAL Consortium
Publisher: BMJ PUBLISHING GROUP
Publication year: 2018
Journal: BMJ
Journal name in source: BMJ-BRITISH MEDICAL JOURNAL
Journal acronym: BMJ-BRIT MED J
Article number: j5757
Volume: 360
Number of pages: 7
ISSN: 1756-1833
DOI: https://doi.org/10.1136/bmj.j5757
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/30040432
OBJECTIVESTo 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.DESIGNAnalysis 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.SETTINGMultiple institutions that were members of international PRACTICAL consortium.PARTICIPANTSAll 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 MEASURESPrediction with hazard score of age of onset of aggressive cancer in validation set.RESULTSIn 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.CONCLUSIONSPolygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
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