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

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.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare no support from any organisation for the submitted work except as follows: DSK and AMD report a research grant from the US Department of Defense, OAA reports research grants from KG Jebsen Stiftelsen, Research Council of Norway, and South East Norway Health Authority, TMS reports honoraria from WebMD for educational content, as well as a research grant from Varian Medical Systems, ASK reports advisory board memberships for Sanofi-Aventis, Dendreon, and Profound, AK reports paid work for Certara Quantitative Systems Pharmacology, DSK reports paid work for Human Longevity, OAA has a patent application (US 20150356243) pending, AMD also applied for this patent application and assigned it to UC San Diego. AMD has additional disclosures outside the present work: founder, equity holder, and advisory board member for CorTechs Labs, advisory board member of Human Longevity, recipient of non-financial research support from General Electric Healthcare; no financial relationships with any companies that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

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Figures

Fig 1

Kaplan-Meier and Cox estimates of prostate cancer-free survival for patients in development set by centile ranges of polygenic hazard score. Centiles are in reference to distribution of score within 11 190 controls aged under 70 in development set. Time of “failure” is age at any diagnosis of prostate cancer. Controls were censored at age of observation. Formal testing of proportionality is described in appendix 1

Fig 2

Positive predictive value of PSA testing for aggressive PCa in validation set. Centiles refer to distribution of polygenic hazard score among young controls in development set. 95% confidence intervals are from random samples of cases in validation set (see methods)