MiR-19, miR-345, miR-519c-5p serum levels predict adverse pathology in prostate cancer patients eligible for active surveillance.

Matthew R Cooperberg,Peter R Carroll,Siao-Yi Wang,Jeffrey P Simko,Hubert Stoppler,Cassandra D Belair,Stephen Shiboski,Robert Blelloch,Janet Cowan

doi:10.1371/journal.pone.0098597

Matthew R Cooperberg, Peter R Carroll + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0098597

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Abstract

Serum microRNAs hold great promise as easily accessible and measurable biomarkers of disease. In prostate cancer, serum miRNA signatures have been associated with the presence of disease as well as correlated with previously validated risk models. However, it is unclear whether miRNAs can provide independent prognostic information beyond current risk models. Here, we focus on a group of low-risk prostate cancer patients who were eligible for active surveillance, but chose surgery. A major criteria for the low risk category is a Gleason score of 6 or lower based on pre-surgical biopsy. However, a third of these patients are upgraded to Gleason 7 on post surgical pathological analysis. Both in a discovery and a validation cohort, we find that pre-surgical serum levels of miR-19, miR-345 and miR-519c-5p can help identify these patients independent of their pre-surgical age, PSA, stage, and percent biopsy involvement. A combination of the three miRNAs increased the area under a receiver operator characteristics curve from 0.77 to 0.94 (p<0.01). Also, when combined with the CAPRA risk model the miRNA signature significantly enhanced prediction of patients with Gleason 7 disease. In-situ hybridizations of matching tumors showed miR-19 upregulation in transformed versus normal-appearing tumor epithelial, but independent of tumor grade suggesting an alternative source for the increase in serum miR-19a/b levels or the release of pre-existing intracellular miR-19a/b upon progression. Together, these data show that serum miRNAs can predict relatively small steps in tumor progression improving the capacity to predict disease risk and, therefore, potentially drive clinical decisions in prostate cancer patients. It will be important to validate these findings in a larger multi-institutional study as well as with independent methodologies.

Highlights

While prostate specific antigen (PSA)-screening has decreased PCa mortality rates in the U.S, it has done so at the cost of detecting early stage/grade PCa that might not affect a patient’s life if untreated [1,2,3,4]
We propose that such a signature has the potential to identify a large number of patients that are unlikely to benefit from immediate surgery, such a conclusion awaits a larger crossinstitutional study with long term follow-up
In order to identify a scoring mechanism accessible to physicians and their patients, we evaluated the utility of adding miRNA values to an established risk model, the Cancer of the Prostate Risk Assessment (CAPRA) score [23]

Summary

Introduction

While prostate specific antigen (PSA)-screening has decreased PCa mortality rates in the U.S, it has done so at the cost of detecting early stage/grade PCa that might not affect a patient’s life if untreated (overdiagnosis) [1,2,3,4]. Treating those with low risk disease results in unnecessary morbidities associated with radical interventions such as surgery or radiation (overtreatment) [5]. In one study of patients meeting criteria for AS but underwent immediate radical prostatectomy 28% were found to have a higher Gleason grade and 21% were found to have T3 disease on surgical pathology [8]

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