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

Seibert TM1,2, Fan CC3,4, Wang Y5, Zuber V5,6, Karunamuni R3,2, Parsons JK7, Eeles RA8,9, Easton DF10, Kote-Jarai Z8, Al Olama AA10,11, Garcia SB10, Muir K12,13, Grönberg H14, Wiklund F14, Aly M14,15,16, Schleutker J17,18,19, Sipeky C17,18, Tammela TL20, Nordestgaard BG21,22, Nielsen SF21,22, Weischer M22, Bisbjerg R23, Røder MA24, Iversen P21,24, Key TJ25, Travis RC25, Neal DE26,27, Donovan JL28, Hamdy FC26, Pharoah P29, Pashayan N30,29, Khaw KT31, Maier C32, Vogel W32, Luedeke M32, Herkommer K33, Kibel AS34, Cybulski C35, Wokolorczyk D35, Kluzniak W35, Cannon-Albright L36,37, Brenner H38,39,40, Cuk K38, Saum KU38, Park JY41, Sellers TA42, Slavov C43, Kaneva R44, Mitev V44, Batra J45, Clements JA45, Spurdle A46,45,47, Teixeira MR48,49, Paulo P48, Maia S48, Pandha H50, Michael A50, Kierzek A50, Karow DS3,51, Mills IG5,52,26, Andreassen OA5, Dale AM1,51,53; PRACTICAL Consortium*.

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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.

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