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

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

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

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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*

Author affiliations

1. Correspondence to: T M Seibert tseibert@ucsd.edu, A M Dale amdale@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.