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A critical evaluation of microRNA biomarkers in non-neoplastic disease.

Haider BA, Baras AS, McCall MN, Hertel JA, Cornish TC, Halushka MK - PLoS ONE (2014)

Bottom Line: Other biomarkers corresponded to common patterns of cellular injury, such as the liver-specific microRNA, miR-122, which was elevated in a disparate set of diseases that injure the liver primarily or secondarily including hepatitis B, hepatitis C, sepsis, and myocardial infarction.Only a subset of reported blood-based microRNA biomarkers have specificity for a particular disease.The remainder of the reported non-neoplastic biomarkers are either biologically implausible, non-specific, or uninterpretable due to limitations of our current understanding of microRNA expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore Maryland, United States of America.

ABSTRACT

Background: MicroRNAs (miRNAs) are small (∼22-nt), stable RNAs that critically modulate post-transcriptional gene regulation. MicroRNAs can be found in the blood as components of serum, plasma and peripheral blood mononuclear cells (PBMCs). Many microRNAs have been reported to be specific biomarkers in a variety of non-neoplastic diseases. To date, no one has globally evaluated these proposed clinical biomarkers for general quality or disease specificity. We hypothesized that the cellular source of circulating microRNAs should correlate with cells involved in specific non-neoplastic disease processes. Appropriate cell expression data would inform on the quality and usefulness of each microRNA as a biomarker for specific diseases. We further hypothesized a useful clinical microRNA biomarker would have specificity to a single disease.

Methods and findings: We identified 416 microRNA biomarkers, of which 192 were unique, in 104 publications covering 57 diseases. One hundred and thirty-nine microRNAs (33%) represented biologically plausible biomarkers, corresponding to non-ubiquitous microRNAs expressed in disease-appropriate cell types. However, at a global level, many of these microRNAs were reported as "specific" biomarkers for two or more unrelated diseases with 6 microRNAs (miR-21, miR-16, miR-146a, miR-155, miR-126 and miR-223) being reported as biomarkers for 9 or more distinct diseases. Other biomarkers corresponded to common patterns of cellular injury, such as the liver-specific microRNA, miR-122, which was elevated in a disparate set of diseases that injure the liver primarily or secondarily including hepatitis B, hepatitis C, sepsis, and myocardial infarction.

Conclusions: Only a subset of reported blood-based microRNA biomarkers have specificity for a particular disease. The remainder of the reported non-neoplastic biomarkers are either biologically implausible, non-specific, or uninterpretable due to limitations of our current understanding of microRNA expression.

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Flow diagram for proposed future microRNA biomarker studies.
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pone-0089565-g005: Flow diagram for proposed future microRNA biomarker studies.

Mentions: We strongly believe that if there was an accessible and comprehensive database of cellular expression patterns for each microRNA, the quality of microRNAs reported as biomarkers would be vastly improved. In the 42 two-step studies (array followed by qRT-PCR), the authors attempted to replicate only a subset of all initial hits. Generally, these were the microRNAs with the highest fold expression changes. If investigators could consider both the relative change in expression and known cellular specificity, it is likely they would have chosen better microRNAs with which to follow up. Therefore, we propose a simple flow chart (Figure 5) taking ideas from the best-designed microRNA biomarker publications and incorporating cell expression localization to create an optimal method of identifying blood-based microRNA biomarkers.


A critical evaluation of microRNA biomarkers in non-neoplastic disease.

Haider BA, Baras AS, McCall MN, Hertel JA, Cornish TC, Halushka MK - PLoS ONE (2014)

Flow diagram for proposed future microRNA biomarker studies.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3935874&req=5

pone-0089565-g005: Flow diagram for proposed future microRNA biomarker studies.
Mentions: We strongly believe that if there was an accessible and comprehensive database of cellular expression patterns for each microRNA, the quality of microRNAs reported as biomarkers would be vastly improved. In the 42 two-step studies (array followed by qRT-PCR), the authors attempted to replicate only a subset of all initial hits. Generally, these were the microRNAs with the highest fold expression changes. If investigators could consider both the relative change in expression and known cellular specificity, it is likely they would have chosen better microRNAs with which to follow up. Therefore, we propose a simple flow chart (Figure 5) taking ideas from the best-designed microRNA biomarker publications and incorporating cell expression localization to create an optimal method of identifying blood-based microRNA biomarkers.

Bottom Line: Other biomarkers corresponded to common patterns of cellular injury, such as the liver-specific microRNA, miR-122, which was elevated in a disparate set of diseases that injure the liver primarily or secondarily including hepatitis B, hepatitis C, sepsis, and myocardial infarction.Only a subset of reported blood-based microRNA biomarkers have specificity for a particular disease.The remainder of the reported non-neoplastic biomarkers are either biologically implausible, non-specific, or uninterpretable due to limitations of our current understanding of microRNA expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore Maryland, United States of America.

ABSTRACT

Background: MicroRNAs (miRNAs) are small (∼22-nt), stable RNAs that critically modulate post-transcriptional gene regulation. MicroRNAs can be found in the blood as components of serum, plasma and peripheral blood mononuclear cells (PBMCs). Many microRNAs have been reported to be specific biomarkers in a variety of non-neoplastic diseases. To date, no one has globally evaluated these proposed clinical biomarkers for general quality or disease specificity. We hypothesized that the cellular source of circulating microRNAs should correlate with cells involved in specific non-neoplastic disease processes. Appropriate cell expression data would inform on the quality and usefulness of each microRNA as a biomarker for specific diseases. We further hypothesized a useful clinical microRNA biomarker would have specificity to a single disease.

Methods and findings: We identified 416 microRNA biomarkers, of which 192 were unique, in 104 publications covering 57 diseases. One hundred and thirty-nine microRNAs (33%) represented biologically plausible biomarkers, corresponding to non-ubiquitous microRNAs expressed in disease-appropriate cell types. However, at a global level, many of these microRNAs were reported as "specific" biomarkers for two or more unrelated diseases with 6 microRNAs (miR-21, miR-16, miR-146a, miR-155, miR-126 and miR-223) being reported as biomarkers for 9 or more distinct diseases. Other biomarkers corresponded to common patterns of cellular injury, such as the liver-specific microRNA, miR-122, which was elevated in a disparate set of diseases that injure the liver primarily or secondarily including hepatitis B, hepatitis C, sepsis, and myocardial infarction.

Conclusions: Only a subset of reported blood-based microRNA biomarkers have specificity for a particular disease. The remainder of the reported non-neoplastic biomarkers are either biologically implausible, non-specific, or uninterpretable due to limitations of our current understanding of microRNA expression.

Show MeSH
Related in: MedlinePlus