Training and validation of a novel 4-miRNA ratio model (MiCaP) for prediction of postoperative outcome in prostate cancer patients

Abstract

BackgroundNew molecular biomarkers for prostate cancer (PC) prognosis are urgently needed. Ratio-based models are attractive, as they require no additional normalization. Here, we train and independently validate a novel 4-miRNA prognostic ratio model for PC.Patients and methodsBy genome-wide miRNA expression profiling of PC tissue samples from 123 men who underwent radical prostatectomy (RP) (PCA123, training cohort), we identified six top candidate prognostic miRNAs and systematically tested their ability to predict postoperative biochemical recurrence (BCR). The best miRNA-based prognostic ratio model (MiCaP) was validated in two independent cohorts (PCA352 and PCA476) including >800 RP patients in total. Clinical end points were BCR and prostate cancer-specific survival (CSS). The prognostic potential of MiCaP was assessed by univariate and multivariate Cox-regression analyses and Kaplan–Meier analyses.ResultsWe identified a 4-miRNA ratio model, MiCaP (miR-23a-3p×miR-10b-5p)/(miR-133a×miR-374b-5p), that predicted time to BCR independently of routine clinicopathologic variables in the training cohort (PCA123) and was successfully validated in two independent RP cohorts. In addition, MiCaP was a significant predictor of CSS in univariate analysis [HR 3.35 (95% CI 1.34 − 8.35), P = 0.0096] and in multivariate analysis [HR 2.43 (95% CI 1.45–4.07), P = 0.0210]. As proof-of-principle, we also analyzed MiCaP in plasma samples from 111 RP patients. A high MiCaP score in plasma was significantly associated with BCR (P = 0.0036, Kaplan–Meier analysis). Limitations include low mortality rates (CSS: 5.4%).ConclusionsWe identified a novel 4-miRNA ratio model (MiCaP) with significant independent prognostic value in three RP cohorts, indicating promising potential to improve PC risk stratification.

A novel combined miRNA and methylation marker panel (miMe) for prediction of prostate cancer outcome after radical prostatectomy

“…The prognostic potential demonstrated for miMe in the present work corroborate and expand on previous PC studies that have reported prognostic potential for the single miRNAs and DNA methylation candidate markers included in miMe . Due to the marked molecular heterogeneity of PC, prognostic multigene panels may perform better than individual markers.…”

“…Gene regulation mediated by miRNA and/or DNA methylation can influence key cellular processes such as growth and differentiation, which in turn may affect tumor development and progression . DNA methylation and miRNAs are attractive sources for biomarker discovery with promising diagnostic and prognostic potential reported for PC in previous studies . As an added potential advantage, both these molecule types can be quantified in archival formalin‐fixed paraffin embedded (FFPE) tissue samples using cost‐effective qPCR‐based methods …”

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

“…MiRNAs have been identified as potential biomarkers and therapeutic targets in cancer and other disease (Cheng et al, ; Schmidt et al, ; Zeng et al, ). Then, whether administration of miR‐34c inhibitor could improve the cognitive deficits in AD model?…”

A five‐microRNA model (pCaP) for predicting prostate cancer aggressiveness using cell‐free urine

“…It has been estimated that miRNAs can modulate the expression of up to 60% of all human mRNAs, often in cell‐specific manners, which makes miRNAs crucial players in key cellular regulatory networks by influencing, for example, cell proliferation and differentiation . Furthermore, dysregulation of miRNAs is a hallmark of PC and has been demonstrated in both tumor tissue samples and in bodily fluids (e.g., serum, plasma and urine) . As each miRNA has the potential to regulate hundreds of target genes, even a slight dysregulation of miRNAs, brought on by, for example, chromosomal alterations or epigenetic changes, can cascade to a plethora of other cellular processes …”

“…7 Furthermore, dysregulation of miRNAs is a hallmark of PC and has been demonstrated in both tumor tissue samples and in bodily fluids (e.g., serum, plasma and urine). [8][9][10][11] As each miRNA has the potential to regulate hundreds of target genes, even a slight dysregulation of miRNAs, brought on by, for example, chromosomal alterations or epigenetic changes, can cascade to a plethora of other cellular processes. 12 In the present study, we investigated whether miRNA levels in cell-free urine samples from PC patients may be used in combination with the serum PSA test to improve prediction of BCR risk after RP.…”