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

Seibert, Tyler M, Fan, Chun Chieh, Wang, Yunpeng, Zuber, Verena, Karunamuni, Roshan, Parsons, J Kellogg, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, ZSofia, Al Olama, Ali Amin , Garcia, Sara Benlloch, Muir, Kenneth, Grönberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo LJ, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bisbjerg, Rasmus, Røder, M Andreas, Iversen, Peter, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Cuk, Katarina, Saum, Kai-Uwe, Park, Jong Y, Sellers, Thomas A, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej, Karow, David S, Mills, Ian G, Andreassen, Ole A and Dale, Anders M (2018) Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts BMJ, 360, j5757. pp. 1-7.

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Objectives: Prostate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to many false positives and overdiagnosis of indolent disease, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patient’s risk. We sought to develop and validate a genetic tool to predict age of aggressive PCa onset and to guide decisions of whom to screen and at what age. Design: Genotype, PCa status, and age were analyzed to select single-nucleotide polymorphisms (SNPs) associated with PCa diagnosis. These SNPs were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (i.e., not eligible for surveillance per NCCN Guidelines; any of: Gleason score ≥7, stage T3-T4, PSA ≥10, nodal metastasis, distant metastasis). The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and screening PSA data. PHS was calculated for these men to test prediction of PCa-free survival. Setting: Multiple, international PRACTICAL consortium member institutions. Participants: All PRACTICAL consortium participants of European ancestry with known age, PCa status, and quality-assured iCOGS array genotype data. Development dataset comprised 31,747 men. Validation dataset comprised 6,411 men. Main outcome measures: PHS prediction of age of onset of aggressive PCa in validation set. Results: In the independent validation set, PHS calculated from 54 SNPs was a highly significant predictor of age at diagnosis of aggressive PCa (z=11.2, p<10-16). When men in the validation set with high PHS (>98th percentile) were compared to those with average PHS (30th-70th percentile), the hazard ratio for aggressive PCa was 2.9. Conclusions:Polygenic hazard scores give personalized genetic risk estimates that predict for age of onset of aggressive PCa.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Seibert, Tyler M
Fan, Chun Chieh
Wang, Yunpeng
Zuber, Verena
Karunamuni, Roshan
Parsons, J Kellogg
Eeles, Rosalind A
Easton, Douglas F
Kote-Jarai, ZSofia
Al Olama, Ali Amin
Garcia, Sara Benlloch
Muir, Kenneth
Grönberg, Henrik
Wiklund, Fredrik
Aly, Markus
Schleutker, Johanna
Sipeky, Csilla
Tammela, Teuvo LJ
Nordestgaard, Børge G
Nielsen, Sune F
Weischer, Maren
Bisbjerg, Rasmus
Røder, M Andreas
Iversen, Peter
Key, Tim J
Travis, Ruth C
Neal, David E
Donovan, Jenny L
Hamdy, Freddie C
Pharoah, Paul
Pashayan, Nora
Khaw, Kay-Tee
Maier, Christiane
Vogel, Walther
Luedeke, Manuel
Herkommer, Kathleen
Kibel, Adam S
Cybulski, Cezary
Wokolorczyk, Dominika
Kluzniak, Wojciech
Cannon-Albright, Lisa
Brenner, Hermann
Cuk, Katarina
Saum, Kai-Uwe
Park, Jong Y
Sellers, Thomas A
Slavov, Chavdar
Kaneva, Radka
Mitev, Vanio
Batra, Jyotsna
Clements, Judith A
Spurdle, Amanda
Teixeira, Manuel R
Paulo, Paula
Maia, Sofia
Karow, David S
Mills, Ian G
Andreassen, Ole A
Dale, Anders M
Date : 10 January 2018
DOI : 10.1136/bmj.j5757
Copyright Disclaimer : Copyright 2018 The Author(s).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:
Uncontrolled Keywords : Prostate cancer; Genetic; Risk; Prediction; Screening; Age; PSA
Depositing User : Melanie Hughes
Date Deposited : 16 Jan 2018 10:04
Last Modified : 26 Jul 2019 11:48

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