1. Polygenic hazard score to guide screening for aggressive - prostate cancer: development and validation in large scale - cohorts
- Author
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Ruth C. Travis, Markus Aly, Chun Chieh Fan, Dominika Wokołorczyk, Fredrik Wiklund, Ole A. Andreassen, Børge G. Nordestgaard, Adam S. Kibel, Amanda B. Spurdle, Verena Zuber, Douglas F. Easton, J. Kellogg Parsons, Agnieszka Michael, Lisa A. Cannon-Albright, Judith A. Clements, Cezary Cybulski, Roshan Karunamuni, M. Andreas Røder, Kathleen Herkommer, Vanio Mitev, Zsofia Kote-Jarai, Walther Vogel, Jong Y. Park, Johanna Schleutker, Tyler M. Seibert, Paul D.P. Pharoah, Hermann Brenner, Ian G. Mills, Kai Uwe Saum, Manuel R. Teixeira, Nora Pashayan, Timothy J. Key, Henrik Grönberg, Maren Weischer, Hardev Pandha, Andrzej M. Kierzek, Manuel Luedeke, Rasmus Bisbjerg, Christiane Maier, Freddie C. Hamdy, Katarina Cuk, Sofia Maia, Paula Paulo, Kay-Tee Khaw, Anders M. Dale, Thomas A. Sellers, Csilla Sipeky, Rosalind A. Eeles, Jenny L Donovan, Wojciech Kluzniak, David E. Neal, Yunpeng Wang, David S. Karow, Teuvo L.J. Tammela, Peter Iversen, Chavdar Slavov, Jyotsna Batra, Sune F. Nielsen, Kenneth Muir, Sara Benlloch Garcia, Radka Kaneva, and Ali Amin Al Olama
- Subjects
0301 basic medicine ,Oncology ,Male ,Percentile ,IMPACT ,urologic and male genital diseases ,Cohort Studies ,Prostate cancer ,PSA ,0302 clinical medicine ,Outcome Assessment, Health Care ,Overdiagnosis ,Age of Onset ,European Continental Ancestry Group/genetics ,Early Detection of Cancer ,risk ,OUTCOMES ,OVERDIAGNOSIS ,Hazard ratio ,Prostatic Neoplasms/blood ,General Medicine ,Middle Aged ,Polymorphism, Single Nucleotide/genetics ,STATISTICS ,ddc ,Prostate-specific antigen ,Editorial ,Centre for Surgical Research ,030220 oncology & carcinogenesis ,TRIAL ,Kallikreins ,Risk assessment ,Life Sciences & Biomedicine ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,Genotype ,European Continental Ancestry Group ,Prostate-Specific Antigen/analysis ,Polymorphism, Single Nucleotide ,Risk Assessment ,White People ,Disease-Free Survival ,03 medical and health sciences ,Outcome Assessment (Health Care) ,Medicine, General & Internal ,AGE ,Predictive Value of Tests ,Internal medicine ,General & Internal Medicine ,medicine ,Journal Article ,BREAST-CANCER ,Humans ,Kallikreins/analysis ,Survival analysis ,Aged ,Science & Technology ,RISK PREDICTION ,business.industry ,screening ,Prostatic Neoplasms ,prediction ,Prostate-Specific Antigen ,medicine.disease ,ta3122 ,PREVENTION ,PRACTICAL Consortium ,Survival Analysis ,030104 developmental biology ,age ,Age of onset ,genetic ,Early Detection of Cancer/methods ,business - 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 Measure 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, P98th 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.
- Published
- 2018
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