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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.

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Abstract

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 :
NameEmailORCID
Seibert, Tyler MUNSPECIFIEDUNSPECIFIED
Fan, Chun ChiehUNSPECIFIEDUNSPECIFIED
Wang, YunpengUNSPECIFIEDUNSPECIFIED
Zuber, VerenaUNSPECIFIEDUNSPECIFIED
Karunamuni, RoshanUNSPECIFIEDUNSPECIFIED
Parsons, J KelloggUNSPECIFIEDUNSPECIFIED
Eeles, Rosalind AUNSPECIFIEDUNSPECIFIED
Easton, Douglas FUNSPECIFIEDUNSPECIFIED
Kote-Jarai, ZSofiaUNSPECIFIEDUNSPECIFIED
Al Olama, Ali AminUNSPECIFIEDUNSPECIFIED
Garcia, Sara BenllochUNSPECIFIEDUNSPECIFIED
Muir, KennethUNSPECIFIEDUNSPECIFIED
Grönberg, HenrikUNSPECIFIEDUNSPECIFIED
Wiklund, FredrikUNSPECIFIEDUNSPECIFIED
Aly, MarkusUNSPECIFIEDUNSPECIFIED
Schleutker, JohannaUNSPECIFIEDUNSPECIFIED
Sipeky, CsillaUNSPECIFIEDUNSPECIFIED
Tammela, Teuvo LJUNSPECIFIEDUNSPECIFIED
Nordestgaard, Børge GUNSPECIFIEDUNSPECIFIED
Nielsen, Sune FUNSPECIFIEDUNSPECIFIED
Weischer, MarenUNSPECIFIEDUNSPECIFIED
Bisbjerg, RasmusUNSPECIFIEDUNSPECIFIED
Røder, M AndreasUNSPECIFIEDUNSPECIFIED
Iversen, PeterUNSPECIFIEDUNSPECIFIED
Key, Tim JUNSPECIFIEDUNSPECIFIED
Travis, Ruth CUNSPECIFIEDUNSPECIFIED
Neal, David EUNSPECIFIEDUNSPECIFIED
Donovan, Jenny LUNSPECIFIEDUNSPECIFIED
Hamdy, Freddie CUNSPECIFIEDUNSPECIFIED
Pharoah, PaulUNSPECIFIEDUNSPECIFIED
Pashayan, NoraUNSPECIFIEDUNSPECIFIED
Khaw, Kay-TeeUNSPECIFIEDUNSPECIFIED
Maier, ChristianeUNSPECIFIEDUNSPECIFIED
Vogel, WaltherUNSPECIFIEDUNSPECIFIED
Luedeke, ManuelUNSPECIFIEDUNSPECIFIED
Herkommer, KathleenUNSPECIFIEDUNSPECIFIED
Kibel, Adam SUNSPECIFIEDUNSPECIFIED
Cybulski, CezaryUNSPECIFIEDUNSPECIFIED
Wokolorczyk, DominikaUNSPECIFIEDUNSPECIFIED
Kluzniak, WojciechUNSPECIFIEDUNSPECIFIED
Cannon-Albright, LisaUNSPECIFIEDUNSPECIFIED
Brenner, HermannUNSPECIFIEDUNSPECIFIED
Cuk, KatarinaUNSPECIFIEDUNSPECIFIED
Saum, Kai-UweUNSPECIFIEDUNSPECIFIED
Park, Jong YUNSPECIFIEDUNSPECIFIED
Sellers, Thomas AUNSPECIFIEDUNSPECIFIED
Slavov, ChavdarUNSPECIFIEDUNSPECIFIED
Kaneva, RadkaUNSPECIFIEDUNSPECIFIED
Mitev, VanioUNSPECIFIEDUNSPECIFIED
Batra, JyotsnaUNSPECIFIEDUNSPECIFIED
Clements, Judith AUNSPECIFIEDUNSPECIFIED
Spurdle, AmandaUNSPECIFIEDUNSPECIFIED
Teixeira, Manuel RUNSPECIFIEDUNSPECIFIED
Paulo, PaulaUNSPECIFIEDUNSPECIFIED
Maia, SofiaUNSPECIFIEDUNSPECIFIED
Pandha, HardevH.Pandha@surrey.ac.ukUNSPECIFIED
Michael, AgnieszkaA.Michael@surrey.ac.ukUNSPECIFIED
Kierzek, AndrzejA.Kierzek@surrey.ac.ukUNSPECIFIED
Karow, David SUNSPECIFIEDUNSPECIFIED
Mills, Ian GUNSPECIFIEDUNSPECIFIED
Andreassen, Ole AUNSPECIFIEDUNSPECIFIED
Dale, Anders MUNSPECIFIEDUNSPECIFIED
Date : 10 January 2018
Identification Number : 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: http://creativecommons.org/licenses/by-nc/4.0/.
Uncontrolled Keywords : Prostate cancer, genetic, risk, prediction, screening, age, PSA
Depositing User : Melanie Hughes
Date Deposited : 16 Jan 2018 10:04
Last Modified : 31 Jan 2018 15:48
URI: http://epubs.surrey.ac.uk/id/eprint/845616

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