Novel diagnostic and prognostic classifiers for prostate cancer identified by genome-wide microRNA profiling.

Helle Kristensen,Anni R. Thomsen,Søren Høyer,Lars Dyrskjøt,Michael Borre,Christa Haldrup,Torben F. Ørntoft,Karina Dalsgaard Sørensen,Peter Mouritzen

doi:10.18632/oncotarget.8953

Abstract

PurposeThis study investigates the diagnostic and prognostic biomarker potential of miRNAs in prostate cancer (PC).ResultsWe identified several new deregulated miRNAs between non-malignant (NM) and PC tissue samples and between more/less aggressive PC subgroups. We also developed and validated a novel 13-miRNA diagnostic classifier with high sensitivity and specificity for PC. Finally, we trained a new 3-miRNA prognostic classifier (miR-185-5p+miR-221-3p+miR-326) that predicted time to biochemical recurrence (BCR) independently of routine clinicopathological variables in a training radical prostatectomy (RP) cohort (n = 126) as well as in two independent validation cohorts (n = 110 and n = 99).Experimental DesignAfter RT-qPCR-based profiling of 752 miRNAs in 13 NM and 134 PC tissue samples (cohort 1), we selected 93 top candidate diagnostic/prognostic miRNAs for validation in two independent patient sets (cohort 2: 19 NM and 138 PC; cohort 3: 28 NM and 113 PC samples). Diagnostic potential was assessed by ROC curve analysis and prognostic potential by Kaplan-Meier, uni- and multivariate Cox regression analyses. BCR after RP was used as endpoint.ConclusionsThis is the first report of a miRNA signature with significant independent prognostic value demonstrated in three PC patient cohorts.

Highlights

Prostate cancer (PC) is the most commonly diagnosed malignancy and the fifth leading cause of cancer-related death among males in western countries [1]
This is the first report of a miRNA signature with significant independent prognostic value demonstrated in three PC patient cohorts
There is an urgent need for new molecular biomarkers that can improve the accuracy of PC detection and better distinguish aggressive PCs that need immediate treatment, e.g. by radical prostatectomy (RP), from non-aggressive PCs that can be safely managed by active surveillance

Summary

Introduction

Prostate cancer (PC) is the most commonly diagnosed malignancy and the fifth leading cause of cancer-related death among males in western countries [1]. PC is diagnosed by histological inspection of prostate needle biopsies, generally indicated by an elevated serum prostate specific antigen (PSA) test and/or a suspect digital rectal examination (DRE). Currently available prognostic indicators (mainly PSA, Gleason score and tumor stage) cannot accurately predict PC aggressiveness at the time of diagnosis, which has led to overtreatment of many indolent PCs partly as a result of increased PSA testing [3, 4]. MicroRNAs comprise an abundant class of endogenous small non-coding RNAs (~22-nt) that control gene expression at the posttranscriptional level [5]. MicroRNAs are transcribed by RNA polymerase II into long, imperfectly paired stem-loop primary miRNAs, which are further processed into hairpin-containing precursor miRNAs, exported to the cytoplasm, and www.impactjournals.com/oncotarget cleaved into a mature ~22-nt miRNA duplex [5]. It has been estimated that up to 60% of human mRNAs are regulated by miRNAs, often in a highly cell type-specific manner, and miRNAs are known to influence key cellular processes, e.g. differentiation, cell cycle progression, and apoptosis [6]

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Conclusion