Validation of the four-miRNA biomarker panel MiCaP for prediction of long-term prostate cancer outcome

Siri H Strand,Anne Karin Ildor Rasmussen,Gitte Kristensen,Klaus Brasso,Linnéa Schmidt,Tina Fuglsang Daugaard,Hein Vincent Stroomberg,Helle Kristensen,Simone Weiss,Michael Borre,Peter Mouritzen,Martin Andreas Røder,Karina Dalsgaard Sørensen

doi:10.1038/s41598-020-67320-y

Siri H Strand, Anne Karin Ildor Rasmussen + Show 11 more

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https://doi.org/10.1038/s41598-020-67320-y

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Improved prostate cancer prognostic biomarkers are urgently needed. We previously identified the four-miRNA prognostic biomarker panel MiCaP ((miR-23a-3p × miR-10b-5p)/(miR-133a-3p × miR-374b-5p)) for prediction of biochemical recurrence (BCR) after radical prostatectomy (RP). Here, we identified an optimal numerical cut-off for MiCaP dichotomisation using a training cohort of 475 RP patients and tested this in an independent cohort of 281 RP patients (PCA281). Kaplan–Meier, uni- and multivariate Cox regression analyses were conducted for multiple endpoints: BCR, metastatic-(mPC) and castration-resistant prostate cancer (CRPC), prostate cancer-specific (PCSS) and overall survival (OS). Functional effects of the four MiCaP miRNAs were assessed by overexpression and inhibition experiments in prostate cancer cell lines. We found the numerical value 5.709 optimal for MiCaP dichotomisation. This was independently validated in PCA281, where a high MiCaP score significantly [and independent of the Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score] predicted BCR, progression to mPC and CRPC, and PCSS, but not OS. Harrell’s C-index increased upon addition of MiCaP to CAPRA-S for all endpoints. Inhibition of miR-23a-3p and miR-10b-5p, and overexpression of miR-133a-3p and miR-374b-5p significantly reduced cell survival. Our results may promote future implementation of a MiCaP-based test for improved prostate cancer risk stratification.

Highlights

Prostate cancer is a significant healthcare problem, globally causing > 300,000 deaths/year[1]
By ROC curve analysis of biochemical recurrence (BCR) status at 36 months in PCA475, we identified a MiCaP score = 5.709 as the optimal cut-off for dichotomisation, as this value maximized both sensitivity and specificity
MiCaP remained a significant predictor of BCR after adjusting for the well-established clinical nomogram, Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score (p = 0.002, Table 1B)

Summary

Introduction

Prostate cancer is a significant healthcare problem, globally causing > 300,000 deaths/year[1]. While many prostate cancers are indolent, a subset progress to metastatic (mPC) and castration-resistant (CRPC) disease, causing significant morbidity and mortality. Dysregulation of miRNA expression is a hallmark of cancer development and p rogression[3,4], and miRNAs have shown promising prognostic biomarker potential in prostate cancer[5,6,7,8,9]. We recently identified the four-miRNA prognostic model MiCaP ((miR-23a-3p × miR-10b-5p)/(miR133a-3p × miR-374b-5p))[9] as an independent predictor of biochemical recurrence (BCR) in radical prostatectomy (RP) p atients[9]. From our previous study[9] Using this cut-off, we tested and validated the prognostic potential of MiCaP in a novel independent cohort of 281 RP patients (PCA281)

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