Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.
- Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA tseibert@ucsd.edu amdale@ucsd.edu.
- Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA.
- NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
- Institute of Cancer Research, London, SM2 5NG, UK.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
- Institute of Population Health, University of Manchester, Manchester, UK.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Department of Medical Biochemistry and Genetics, Institute of Biomedicine, Kiinamyllynkatu 10, FI-20014 University of Turku, Finland.
- Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Finland.
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
- Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
- Copenhagen Prostate Cancer Centre, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford OX3 7LF, UK.
- Nuffield Department of Surgical Sciences, Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK.
- School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
- University College London, Department of Applied Health Research, London WC1E 7HB, UK.
- Clinical Gerontology Unit, University of Cambridge, Cambridge UK.
- Institute of Human Genetics, University Hospital of Ulm, Ulm, Germany.
- Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany.
- Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, 75 Francis Street, Boston, MA 02115, USA.
- International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
- Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
- Office of the Center Director, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
- Department of Urology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria.
- Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, 2 Zdrave Str, 1431 Sofia, Bulgaria.
- Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia.
- Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
- University of Surrey, Guildford, Surrey, GU2 7XH.
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.