Comparative Study

. 2018 Jan 10:360:j5757.

doi: 10.1136/bmj.j5757.

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

Tyler M Seibert^{1

2}, Chun Chieh Fan^{3

4}, Yunpeng Wang⁵, Verena Zuber^{5

6}, Roshan Karunamuni^{3

2}, J Kellogg Parsons⁷, Rosalind A Eeles^{8

9}, Douglas F Easton¹⁰, ZSofia Kote-Jarai⁸, Ali Amin Al Olama^{10

11}, Sara Benlloch Garcia¹⁰, Kenneth Muir^{12

13}, Henrik Grönberg¹⁴, Fredrik Wiklund¹⁴, Markus Aly^{14

15

16}, Johanna Schleutker^{17

18

19}, Csilla Sipeky^{17

18}, Teuvo Lj Tammela²⁰, Børge G Nordestgaard^{21

22}, Sune F Nielsen^{21

22}, Maren Weischer²², Rasmus Bisbjerg²³, M Andreas Røder²⁴, Peter Iversen^{21

24}, Tim J Key²⁵, Ruth C Travis²⁵, David E Neal^{26

27}, Jenny L Donovan²⁸, Freddie C Hamdy²⁶, Paul Pharoah²⁹, Nora Pashayan^{30

29}, Kay-Tee Khaw³¹, Christiane Maier³², Walther Vogel³², Manuel Luedeke³², Kathleen Herkommer³³, Adam S Kibel³⁴, Cezary Cybulski³⁵, Dominika Wokolorczyk³⁵, Wojciech Kluzniak³⁵, Lisa Cannon-Albright^{36

37}, Hermann Brenner^{38

39

40}, Katarina Cuk³⁸, Kai-Uwe Saum³⁸, Jong Y Park⁴¹, Thomas A Sellers⁴², Chavdar Slavov⁴³, Radka Kaneva⁴⁴, Vanio Mitev⁴⁴, Jyotsna Batra⁴⁵, Judith A Clements⁴⁵, Amanda Spurdle^{46

45

47}, Manuel R Teixeira^{48

49}, Paula Paulo⁴⁸, Sofia Maia⁴⁸, Hardev Pandha⁵⁰, Agnieszka Michael⁵⁰, Andrzej Kierzek⁵⁰, David S Karow^{3

51}, Ian G Mills^{5

52

26}, Ole A Andreassen⁵, Anders M Dale^{1

51

53}; PRACTICAL Consortium*

Affiliations

¹ Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA tseibert@ucsd.edu amdale@ucsd.edu.
² Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA.
³ Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA.
⁴ Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
⁵ NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁶ MRC Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
⁷ Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
⁸ Institute of Cancer Research, London, SM2 5NG, UK.
⁹ Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
¹⁰ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
¹¹ Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, R3, Box 83, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹² Institute of Population Health, University of Manchester, Manchester, UK.
¹³ Warwick Medical School, University of Warwick, Coventry, UK.
¹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Department of Molecular Medicine and Surgery, Solna, 171 76 Stockholm, Sweden.
¹⁶ Department of Urology, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden.
¹⁷ Department of Medical Biochemistry and Genetics, Institute of Biomedicine, Kiinamyllynkatu 10, FI-20014 University of Turku, Finland.
¹⁸ Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
¹⁹ BioMediTech, 30014 University of Tampere, Tampere, Finland.
²⁰ Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Finland.
²¹ Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
²² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²³ Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²⁴ Copenhagen Prostate Cancer Centre, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²⁵ Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford OX3 7LF, UK.
²⁶ Nuffield Department of Surgical Sciences, Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK.
²⁷ University of Cambridge, Department of Oncology, Box 279, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
²⁸ School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
²⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
³⁰ University College London, Department of Applied Health Research, London WC1E 7HB, UK.
³¹ Clinical Gerontology Unit, University of Cambridge, Cambridge UK.
³² Institute of Human Genetics, University Hospital of Ulm, Ulm, Germany.
³³ Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany.
³⁴ Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, 75 Francis Street, Boston, MA 02115, USA.
³⁵ International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁶ Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
³⁷ George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
³⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁴⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴¹ Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁴² Office of the Center Director, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁴³ Department of Urology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria.
⁴⁴ Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, 2 Zdrave Str, 1431 Sofia, Bulgaria.
⁴⁵ Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia.
⁴⁶ Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
⁴⁷ Australian Prostate Cancer BioResource, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia.
⁴⁸ Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
⁴⁹ Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
⁵⁰ University of Surrey, Guildford, Surrey, GU2 7XH.
⁵¹ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
⁵² Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
⁵³ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.

PMID: 29321194
PMCID: PMC5759091
DOI: 10.1136/bmj.j5757

Comparative Study

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

Tyler M Seibert et al. BMJ. 2018.

. 2018 Jan 10:360:j5757.

doi: 10.1136/bmj.j5757.

Authors

Affiliations

¹ Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA tseibert@ucsd.edu amdale@ucsd.edu.
² Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, USA.
³ Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA.
⁴ Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
⁵ NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁶ MRC Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
⁷ Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
⁸ Institute of Cancer Research, London, SM2 5NG, UK.
⁹ Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
¹⁰ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
¹¹ Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, R3, Box 83, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹² Institute of Population Health, University of Manchester, Manchester, UK.
¹³ Warwick Medical School, University of Warwick, Coventry, UK.
¹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁵ Department of Molecular Medicine and Surgery, Solna, 171 76 Stockholm, Sweden.
¹⁶ Department of Urology, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden.
¹⁷ Department of Medical Biochemistry and Genetics, Institute of Biomedicine, Kiinamyllynkatu 10, FI-20014 University of Turku, Finland.
¹⁸ Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
¹⁹ BioMediTech, 30014 University of Tampere, Tampere, Finland.
²⁰ Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Finland.
²¹ Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
²² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²³ Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²⁴ Copenhagen Prostate Cancer Centre, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²⁵ Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford OX3 7LF, UK.
²⁶ Nuffield Department of Surgical Sciences, Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK.
²⁷ University of Cambridge, Department of Oncology, Box 279, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
²⁸ School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK.
²⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
³⁰ University College London, Department of Applied Health Research, London WC1E 7HB, UK.
³¹ Clinical Gerontology Unit, University of Cambridge, Cambridge UK.
³² Institute of Human Genetics, University Hospital of Ulm, Ulm, Germany.
³³ Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany.
³⁴ Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, 75 Francis Street, Boston, MA 02115, USA.
³⁵ International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁶ Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
³⁷ George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
³⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁴⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴¹ Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁴² Office of the Center Director, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁴³ Department of Urology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria.
⁴⁴ Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, 2 Zdrave Str, 1431 Sofia, Bulgaria.
⁴⁵ Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia.
⁴⁶ Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
⁴⁷ Australian Prostate Cancer BioResource, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Australia.
⁴⁸ Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
⁴⁹ Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
⁵⁰ University of Surrey, Guildford, Surrey, GU2 7XH.
⁵¹ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
⁵² Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
⁵³ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.

PMID: 29321194
PMCID: PMC5759091
DOI: 10.1136/bmj.j5757

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.

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

**Fig 1**
Kaplan-Meier and Cox estimates of prostate cancer-free survival for patients in development set by centile ranges of polygenic hazard score. Centiles are in reference to distribution of score within 11 190 controls aged under 70 in development set. Time of “failure” is age at any diagnosis of prostate cancer. Controls were censored at age of observation. Formal testing of proportionality is described in appendix 1

**Fig 2**
Positive predictive value of PSA testing for aggressive PCa in validation set. Centiles refer to distribution of polygenic hazard score among young controls in development set. 95% confidence intervals are from random samples of cases in validation set (see methods)

See this image and copyright information in PMC

Comment in

Development and validation of a polygenic hazard score for aggressive prostate cancer identification.
Mohamed NE, Tewari AK, Yadav KK. Mohamed NE, et al. Transl Cancer Res. 2019 Mar;8(Suppl 2):S124-S125. doi: 10.21037/tcr.2018.11.34. Transl Cancer Res. 2019. PMID: 35117080 Free PMC article. No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous