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

BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.j5757 (Published 10 January 2018) Cite this as: BMJ 2018;360:j5757
  1. Tyler M Seibert, resident physician1 2,
  2. Chun Chieh Fan, research scientist1 3,
  3. Yunpeng Wang, postdoctoral fellow4,
  4. Verena Zuber, postdoctoral fellow4 5,
  5. Roshan Karunamuni, postdoctoral fellow1 2,
  6. J Kellogg Parsons, professor6,
  7. Rosalind A Eeles, professor7 8,
  8. Douglas F Easton, professor9,
  9. ZSofia Kote-Jarai, researcher7,
  10. Ali Amin Al Olama, research associate9 10,
  11. Sara Benlloch Garcia, researcher9,
  12. Kenneth Muir, professor11 12,
  13. Henrik Grönberg, professor13,
  14. Fredrik Wiklund, associate professor13,
  15. Markus Aly, researcher13 14 15,
  16. Johanna Schleutker, professor16 17 18,
  17. Csilla Sipeky, adjunct professor16 17,
  18. Teuvo LJ Tammela, professor19,
  19. Børge G Nordestgaard, professor20 21,
  20. Sune F Nielsen, researcher20 21,
  21. Maren Weischer, resident physician21,
  22. Rasmus Bisbjerg, consultant22,
  23. M Andreas Røder, researcher23,
  24. Peter Iversen, professor20 23,
  25. Tim J Key, professor24,
  26. Ruth C Travis, associate professor24,
  27. David E Neal, professor25 26,
  28. Jenny L Donovan, professor27,
  29. Freddie C Hamdy, professor25,
  30. Paul Pharoah, professor28,
  31. Nora Pashayan, clinical reader in applied health research29 28,
  32. Kay-Tee Khaw, professor30,
  33. Christiane Maier, researcher31,
  34. Walther Vogel, professor31,
  35. Manuel Luedeke, researcher31,
  36. Kathleen Herkommer, researcher32,
  37. Adam S Kibel, professor33,
  38. Cezary Cybulski, professor34,
  39. Dominika Wokolorczyk, assistant professor34,
  40. Wojciech Kluzniak, assistant professor34,
  41. Lisa Cannon-Albright, professor35 36,
  42. Hermann Brenner, professor37 38 39,
  43. Katarina Cuk, postdoctoral fellow37,
  44. Kai-Uwe Saum, researcher37,
  45. Jong Y Park, associate professor40,
  46. Thomas A Sellers, cancer center director41,
  47. Chavdar Slavov, researcher42,
  48. Radka Kaneva, researcher43,
  49. Vanio Mitev, researcher43,
  50. Jyotsna Batra, researcher44,
  51. Judith A Clements, professor44,
  52. Amanda Spurdle, professor, Australian Prostate Cancer BioResource, researcher4544 46,
  53. Manuel R Teixeira, professor47 48,
  54. Paula Paulo, researcher47,
  55. Sofia Maia, researcher47,
  56. Hardev Pandha, professor49,
  57. Agnieszka Michael, researcher49,
  58. Andrzej Kierzek, professor49,
  59. David S Karow, associate professor1 50,
  60. Ian G Mills, associate professor4 51 25,
  61. Ole A Andreassen, professor4,
  62. Anders M Dale, professor1 50 52,
  63. The PRACTICAL Consortium*
  1. 1Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA
  2. 2Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA
  3. 3Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA
  4. 4NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway
  5. 5MRC Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK
  6. 6Department of Surgery, University of California, San Diego, La Jolla, CA, USA
  7. 7Institute of Cancer Research, London, SM2 5NG, UK
  8. 8Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK
  9. 9Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
  10. 10Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, R3, Box 83, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  11. 11Institute of Population Health, University of Manchester, Manchester, UK
  12. 12Warwick Medical School, University of Warwick, Coventry, UK
  13. 13Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  14. 14Department of Molecular Medicine and Surgery, Solna, 171 76 Stockholm, Sweden
  15. 15Department of Urology, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden
  16. 16Department of Medical Biochemistry and Genetics, Institute of Biomedicine, Kiinamyllynkatu 10, FI-20014 University of Turku, Finland
  17. 17Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland
  18. 18BioMediTech, 30014 University of Tampere, Tampere, Finland
  19. 19Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Finland
  20. 20Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  21. 21Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  22. 22Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  23. 23Copenhagen Prostate Cancer Centre, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  24. 24Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford OX3 7LF, UK
  25. 25Nuffield Department of Surgical Sciences, Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK
  26. 26University of Cambridge, Department of Oncology, Box 279, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
  27. 27School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK
  28. 28Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  29. 29University College London, Department of Applied Health Research, London WC1E 7HB, UK
  30. 30Clinical Gerontology Unit, University of Cambridge, Cambridge UK
  31. 31Institute of Human Genetics, University Hospital of Ulm, Ulm, Germany
  32. 32Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany
  33. 33Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, 75 Francis Street, Boston, MA 02115, USA
  34. 34International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  35. 35Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
  36. 36George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA
  37. 37Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  38. 38Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
  39. 39German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  40. 40Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
  41. 41Office of the Center Director, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
  42. 42Department of Urology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria
  43. 43Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, 2 Zdrave Str, 1431 Sofia, Bulgaria
  44. 44Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia
  45. 45Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia
  46. 46Australian Prostate Cancer BioResource, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia
  47. 47Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  48. 48Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
  49. 49University of Surrey, Guildford, Surrey, GU2 7XH
  50. 50Department of Radiology, University of California, San Diego, La Jolla, CA, USA
  51. 51Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK
  52. 52Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
  1. Correspondence to: T M Seibert tseibert{at}ucsd.edu, A M Dale amdale{at}ucsd.edu, Center for Multimodal Imaging and Genetics, Altman CTRI Building 4W 102, 9500 Gilman Drive, Mail Code 0841, La Jolla, CA 92093-0841, USA
  • Accepted 4 December 2017

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.

Footnotes

  • Contributors: TMS, CCF, VZ, DSK, IGM, OAA, and AMD designed the study. RAE, DFE, ZSKJ, AAAO, SBG, KM, HG, FW, MA, JS, CSi, TLJT, BGN, SFN, MW, RB, MAR, PI, TJK, RCT, DEN, JLD, FCH, PPh, NP, KTK, CM, WV, ML, KH, ASK, CC, DW, WK, LCA, HB, KC, KUS, JYP, TAS, CSI, RKan, VM, B, JAC, AS, APCBR, MRT, PPa, SM, HP, AM, and AK collected the data. TMS, CCF, IGM, OAA, and AMD performed the literature search. TMS, CCF, YW, VZ, RKar, DSK, and AMD performed the data analysis. TMS, CCF, RKar, JKP, DSK, OAA, and AMD interpreted the data. TMS, RKar, JKP, DSK, OAA, and AMD created the figures. TMS, CCF, OAA, and AMD wrote the manuscript. All authors reviewed the manuscript, added appropriate revisions, agreed to submission for publication, and approved the final version. TMS and AMD are guarantors.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare no support from any organisation for the submitted work except as follows: DSK and AMD report a research grant from the US Department of Defense, OAA reports research grants from KG Jebsen Stiftelsen, Research Council of Norway, and South East Norway Health Authority, TMS reports honoraria from WebMD for educational content, as well as a research grant from Varian Medical Systems, ASK reports advisory board memberships for Sanofi-Aventis, Dendreon, and Profound, AK reports paid work for Certara Quantitative Systems Pharmacology, DSK reports paid work for Human Longevity, OAA has a patent application (US 20150356243) pending, AMD also applied for this patent application and assigned it to UC San Diego. AMD has additional disclosures outside the present work: founder, equity holder, and advisory board member for CorTechs Labs, advisory board member of Human Longevity, recipient of non-financial research support from General Electric Healthcare; no financial relationships with any companies that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethics approval: Not required.

  • Funding: This study was funded in part by grants from the US Department of Defense (W81XWH-13-1-0391), Prostate Cancer Foundation, the Research Council of Norway (223273), KG Jebsen Stiftelsen, and South East Norway Health Authority. Funding for the PRACTICAL consortium member studies is detailed in appendix 2.

  • Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

  • Data sharing: No additional data available.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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