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000131811 0247_ $$2ISSN$$a1756-1833
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000131811 0247_ $$2doi$$aDOI: 10.1136/bmj.j5757 
000131811 037__ $$aDKFZ-2018-00106
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000131811 1001_ $$aSeibert, Tyler M$$b0
000131811 245__ $$aPolygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.
000131811 260__ $$aMalden$$bBMJ Publishing Group$$c2018
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000131811 520__ $$aTo 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.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.Multiple institutions that were members of international PRACTICAL consortium.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.Prediction with hazard score of age of onset of aggressive cancer in validation set.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.Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
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000131811 7001_ $$aFan, Chun Chieh$$b1
000131811 7001_ $$aWang, Yunpeng$$b2
000131811 7001_ $$aZuber, Verena$$b3
000131811 7001_ $$aKarunamuni, Roshan$$b4
000131811 7001_ $$aParsons, J Kellogg$$b5
000131811 7001_ $$aEeles, Rosalind A$$b6
000131811 7001_ $$aEaston, Douglas F$$b7
000131811 7001_ $$aKote-Jarai, ZSofia$$b8
000131811 7001_ $$aAl Olama, Ali Amin$$b9
000131811 7001_ $$aGarcia, Sara Benlloch$$b10
000131811 7001_ $$aMuir, Kenneth$$b11
000131811 7001_ $$aGrönberg, Henrik$$b12
000131811 7001_ $$aWiklund, Fredrik$$b13
000131811 7001_ $$aAly, Markus$$b14
000131811 7001_ $$aSchleutker, Johanna$$b15
000131811 7001_ $$aSipeky, Csilla$$b16
000131811 7001_ $$aTammela, Teuvo Lj$$b17
000131811 7001_ $$aNordestgaard, Børge G$$b18
000131811 7001_ $$aNielsen, Sune F$$b19
000131811 7001_ $$aWeischer, Maren$$b20
000131811 7001_ $$aBisbjerg, Rasmus$$b21
000131811 7001_ $$aRøder, M Andreas$$b22
000131811 7001_ $$aIversen, Peter$$b23
000131811 7001_ $$aKey, Tim J$$b24
000131811 7001_ $$aTravis, Ruth C$$b25
000131811 7001_ $$aNeal, David E$$b26
000131811 7001_ $$aDonovan, Jenny L$$b27
000131811 7001_ $$aHamdy, Freddie C$$b28
000131811 7001_ $$aPharoah, Paul$$b29
000131811 7001_ $$aPashayan, Nora$$b30
000131811 7001_ $$aKhaw, Kay-Tee$$b31
000131811 7001_ $$aMaier, Christiane$$b32
000131811 7001_ $$aVogel, Walther$$b33
000131811 7001_ $$aLuedeke, Manuel$$b34
000131811 7001_ $$aHerkommer, Kathleen$$b35
000131811 7001_ $$aKibel, Adam S$$b36
000131811 7001_ $$aCybulski, Cezary$$b37
000131811 7001_ $$aWokolorczyk, Dominika$$b38
000131811 7001_ $$aKluzniak, Wojciech$$b39
000131811 7001_ $$aCannon-Albright, Lisa$$b40
000131811 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b41$$udkfz
000131811 7001_ $$0P:(DE-He78)0a8ada1f5d2ea05fc3af10cd808bfa9a$$aCuk, Katarina$$b42$$udkfz
000131811 7001_ $$0P:(DE-He78)97343bbd9545a4b87574e74329dabfd1$$aSaum, Kai-Uwe$$b43$$udkfz
000131811 7001_ $$aPark, Jong Y$$b44
000131811 7001_ $$aSellers, Thomas A$$b45
000131811 7001_ $$aSlavov, Chavdar$$b46
000131811 7001_ $$aKaneva, Radka$$b47
000131811 7001_ $$aMitev, Vanio$$b48
000131811 7001_ $$aBatra, Jyotsna$$b49
000131811 7001_ $$aClements, Judith A$$b50
000131811 7001_ $$aSpurdle, Amanda$$b51
000131811 7001_ $$aTeixeira, Manuel R$$b52
000131811 7001_ $$aPaulo, Paula$$b53
000131811 7001_ $$aMaia, Sofia$$b54
000131811 7001_ $$aPandha, Hardev$$b55
000131811 7001_ $$aMichael, Agnieszka$$b56
000131811 7001_ $$aKierzek, Andrzej$$b57
000131811 7001_ $$aKarow, David S$$b58
000131811 7001_ $$aMills, Ian G$$b59
000131811 7001_ $$aAndreassen, Ole A$$b60
000131811 7001_ $$aDale, Anders M$$b61
000131811 7001_ $$aConsortium, PRACTICAL$$b62$$eCollaboration Author
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