A review of expression profiling of circulating microRNAs in men with prostate cancer


The authors of the present article carefully reviewed the published literature on the circulating microRNAs (miRNAs) in patients with prostate cancer. They summarised 10 studies and discussed the use of miRNAs as potential non-invasive diagnostic, prognostic, and monitoring biomarkers. As is generally the case when new disease markers have been analysed, the authors came to two conclusions: these first data of miRNA measurements in serum of patients with prostate cancer are promising, but further research is needed to prove their utility in clinical practice. The data in table 1 underline this statement. In the 10 studies reported, 35 different miRNAs in serum/plasma were described as increased and six as decreased. However, only four miRNAs (mature microRNA (miR)-21, miR-141, miR-221, miR-375) were found to be changed in at least two studies, but not always consistently in the same direction (e.g. miR-141). These figures indicate the fact that this field of research is still in its infancy if one considers that 2154 mature human miRNAs are now registered in the current miRNA database (http://www.mirbase.org).

The heterogeneity of the studies might be one reason for the disparity of results. But a detailed analysis of these studies showed that the diversity of methods used is obviously much more significant, an issue less common to most urologists. The limitation of space to discuss all problems let me stress only this issue. In most of the articles, the pre-analytical and analytical procedures were only partly outlined according to the Standard Reporting Diagnostic Accuracy (STARD) guideline [1], so that it is difficult for the reader to assess the accuracy of the results. Highly ranked analytically oriented journals (e.g. Clinical Chemistry) meanwhile require a completed checklist with 25 items referring to the study design, description of the pre-analytical and analytical variables, and evaluation of data as a precondition for the publication of a manuscript about studies on new diagnostic tests. Clinically oriented journals should be encouraged likewise to demand similarly such a checklist from their authors. A convincing example for this necessity can be illustrated by the actual topic ‘circulating’ miRNAs. What does it mean ‘circulating'? Circulating miRNAs are considered cell-free miRNAs released from organs and tissues into the blood stream, while potential changes occur under organ- or tissue-related physiological and pathological conditions or systemic influences. In the studies summarised in the review, both serum and plasma samples collected and processed under very different or partly indefinitely described conditions (various blood collection devices, time interval between phlebotomy and centrifugation, storage temperature during this period, centrifugation conditions, e.g. speed, duration, and temperature etc.) were uniformly defined as sources of ‘circulating’ miRNAs. The pre-analytical differences of samplings alone give rise to distinctly interfering effects by varying levels of miRNAs from leukocytes, erythrocytes, and platelets, respectively [2-4]. The true cell-free circulating miRNAs could be confounded by cellular miRNAs from blood cells either released from them or as contaminating cellular particles insufficiently removed by inappropriate centrifugation [4]. Hence it would not be surprising if the ignorance of decisive pre-analytical variables led to implausible final results and lacking interchangeability of data between studies. That impairs the introduction of actually promising biomarkers as tests in clinical practice. Such detrimental effect has been seen for the circulating free DNA or matrix metalloproteinases [5, 6]. Similarly, the use of different analytical techniques without traceability, especially for the isolation of miRNAs, might have an additional aggravating effect on the lacking comparability of data. Thus, it is thanks to the authors of this review, as they drew our attention to the weak spots of the studies. Thus, the urgent appeal is made to urologists and laboratory scientists to cooperatively solve these defined problems, thereby creating the basis for the translation of basic science discoveries into promising clinical applications.