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.

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

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Age dependence of modern clinical risk groups for localized prostate cancer—A population‐based study

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“…Effective prostate cancer (PCa) screening seeks to identify clinically significant and potentially lethal cases requiring treatment while avoiding the overdiagnosis of more indolent, lower risk cases eligible for active surveillance . Disease aggressiveness is accounted for in clinical decision making with widely used risk stratification schemes .…”

Translating genomic risk into an early detection strategy for sarcoma

“…The remaining unexplained congenital cancer risk may arise from the aggregate influence of many common variants of small effect, which in combination can significantly affect an individual's cancer risk. Emerging evidence suggests that this model is accurate in many cancers, with common loci contributing clinically significant hazard for breast, colorectal, and prostate cancers. Critically, polygenic risk estimates based on these common loci provide orthogonal information to family history, and so can be incorporated into a summative assessment of cancer risk that integrates rare and common genetic variation, family history, and environmental exposures.…”

“…Emerging evidence suggests that this model is accurate in many cancers, with common loci contributing clinically significant hazard for breast, colorectal, and prostate cancers. Critically, polygenic risk estimates based on these common loci provide orthogonal information to family history, and so can be incorporated into a summative assessment of cancer risk that integrates rare and common genetic variation, family history, and environmental exposures. Early explorations in this area are promising, with a measure of colorectal cancer risk that integrates both polygenic and familial components able to distinguish high‐ and low‐risk groups with a relative risk of 6.1‐fold .…”