Focus on miRNA biomarkers

FirePlex miRNA assay guide:

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Why do miRNAs make good biomarkers?

Biomarkers have the potential to allow us to predict, diagnose or monitor disease. In particular, there is a need to discover biomarkers that can be used to detect diseases for which early diagnosis is crucial or diagnosis is currently difficult.

As miRNA research has expanded into a huge number of disease areas, it has become clear that expression levels of certain miRNAs are altered in many diseases. As such, the potential of these small non-coding RNAs as biomarkers has become obvious, and exploiting it has become a focus for researchers around the globe.

_{"Expression levels of certain miRNAs are altered in many diseases"}

Alongside altered expression under different disease states, miRNAs have other features that make them ideally suited as biomarkers. miRNAs are present in biofluids including blood, urine and saliva, allowing relatively non-invasive sample collection. In addition to their accessibility, miRNAs are highly stable in biofluids and in collected samples making miRNAs relatively easy to work with and assay via a range of different methods.

With these ideal biomarker qualities, it is little wonder that such a large research effort is going into identifying potential miRNA biomarkers for diseases.

Promising miRNA biomarkers in cancer

Oncologists are leading the way in identifying and validating miRNA signatures to diagnose and monitor disease. This is being driven by the importance of early cancer diagnosis and the need to be able to distinguish between different forms of cancer.

Discovering miRNA expression patterns that are unique to a particular cancer is an important first step in identifying biomarker signatures that will be effective in its detection, and there is significant evidence that various cancers have distinct miRNA profiles (Mitchell et al., 2008). As an example, two recently published papers have identified differences in miRNA expression in prostate cancer.

A particular problem with prostate cancer is the difficulty of determining whether the cancer is an aggressive form that requires immediate treatment, or a low-grade cancer. Mihelich et al. (2015) investigated miRNA biomarkers as a possible solution to this problem. They identified 14 miRNAs that were exclusively present in serum from patients with low-grade compared with high-grade prostatic cancer. This is a great advancement and we now have an miRNA signature that may one day be used to prevent the overtreatment of patients with low grade prostate cancer.

Another study looked at a separate issue in prostate cancer: how to tell when the cancer has metastasized to the bone. Bone metastasis is common in prostate cancer and is associated with decreased survival. The authors found that a unique combination of miRNAs involving changes in miR-15, miR-16 and miR-21 was associated with bone metastasis (Bonci et al., 2015).

Large-scale validation studies: bringing miRNA biomarkers closer to clinical use

Research into lung cancer miRNA biomarkers has taken an extra step towards the clinic by taking potential miRNA biomarkers and trialing them in large-scale validation studies. Lung cancer is notoriously difficult to detect in its early stages and these studies have attempted to answer the question of whether previously identified miRNA biomarkers can actually predict disease among high-risk individuals.

_{"Promising results mean that early detection of lung cancer is now that little bit closer"}

Montani et al., (2015) used participants from the Continuous Observation of Smoking Subjects lung cancer screening program to test a  13-miRNA signature. They found that monitoring this combination of miRNAs could detect the disease with an overall accuracy of 74.9%. A similar study as part of the Multicenter Italian Lung Detection randomized clinical trial found that a certain plasma miRNA signature could detect lung cancer with 87% sensitivity and 81% specificity (Sozzi et al., 2014). These promising results mean that early detection of lung cancer is now that little bit closer.

Potential miRNA biomarkers for more than just cancer

Cancer isn't the only research area that looks set to benefit from  miRNA biomarkers. Unique biomarker signatures have been identified in various diseases, including numerous cardiovascular and neurological diseases (Min & Chan, 2015; Rao et al., 2013).

One particularly active area of miRNA biomarker research is in Alzheimer's disease. An effective method to screen for Alzheimer's early in disease progression may aid in the development of much-needed therapeutic and preventative drugs (Blennow et al., 2015; Framminella et al., 2015).

In a recent study, miRNAs present in the cerebrospinal fluid (CSF) were profiled to detect expression differences between Alzheimer's disease patients and controls. By taking forward a panel of three miRNAs, the researchers were able to identify Alzheimer's disease in CSF with 95.5% accuracy (Denk et al., 2015).

The future of miRNA biomarkers

There is a huge amount of research being carried out currently to find potential biomarkers for disease. As more miRNAs are tested in large-scale validation studies and clinical trials, we get closer to effective clinical miRNA biomarkers becoming a reality.

To keep up with this fast paced area of research, tools are required that allow the profiling of multiple miRNAs in a range of clinical samples. Our Multiplex miRNA Assays using Firefly technology can be used to detect miRNAs directly from crude biofluids with streamlined workflow and no need for RNA purification.

_{Streamlined workflow with no RNA purification: profile miRNAs directly from crude biofluids}
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References

• Blennow K, Dubois, B Fagan AM, Lewczuk P, de Leon MJ, Hampel H (2015). Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement 11, 58–69.
• Bonci D, Coppola V, Patrizii M, Addario A, Cannistraci A, Francescangeli F, Pecci R, Muto G, Collura D, Bedini R, Zeuner A, Valtieri M, Sentinelli S, Benassi MS, Gallucci M, Carlini P, Piccolo S, De Maria R (2015). A microRNA code for prostate cancer metastasis [published online ahead of print 15 June, 2015]. Oncogene, doi:10.1038/onc.2015.176.
• Denk J, Boelmans K, Siegismund C, Lassner D, Arlt S, Jahn H (2015). MicroRNA profiling of CSF reveals potential biomarkers to detect Alzheimer’s disease. PLoS ONE 10, e0126423.
• Femminella GD, Ferrara N, Rengo G (2015). The emerging role of microRNAs in Alzheimer’s disease. Front Physiol 6, 40.
• Mihelich BL, Maranville JC, Nolley R, Peehl DM, Nonn L (2015). Elevated serum microRNA levels associate with absence of high-grade prostate cancer in a retrospective cohort. PLoS ONE 10, e0124245.
• Min PK, Chan SY (2015). The biology of circulating microRNAs in cardiovascular disease. Eur J Clin Invest 45, 860–74.
• Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008). Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105, 10513–8.
• Montani F, Marzi MJ, Dezi F, Dama E, Carletti RM, Bonizzi G, Bertolotti R, Bellomi M, Rampinelli C, Maisonneuve P, Spaggiari L, Veronesi G, Nicassio F, Di Fiore P, Bianchi F (2015). miR-Test: A blood test for lung cancer early detection. J Natl Cancer Inst 107.
• Rao P, Benito E, Fischer A (2013). MicroRNAs as biomarkers for CNS disease. Front Mol Neurosci 6, 39.
• Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M, Sverzellati N, Marchiano A, Negri E, La Vecchia C, Pastorino U (2014). Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J Clin Oncol 32, 768–773.