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MicroRNA as an identifying biomarker for cancer

Ulysses S. Grant once explained that the “art of war is simple enough. Find out where your enemy is. Get at him as soon as you can. Strike him as hard as you can, and keep moving on.” Cancer is a war, on its own. The patients have to go through immense distress and there is always collateral damage to their families. A significant problem with dealing with cancer is detection because in the early stages, cancer is usually easily treated. However, as the cancer has time to grow and possibly metastasize, the chances for survival exponentially decrease. Many recent breakthroughs in the field of detecting cancer have shown that microRNA (miRNA) can be used to diagnose where the cancer is, what subtype the cancer possibly is, and what course of treatment would be most effective.

MicroRNAs (miRNAs) are small regulatory RNA molecules, which are about 22 nucleotides long, that modulate the activity of specific mRNA targets and play important roles in many physiologic and pathologic processes [1]. MiRNA can be used as a biomarker because its expression is usually dysregulated in cancerous cells. According to an article published by a research institute in Cambridge, U.K., miRNAs have tumor suppressing potential and in cancer there is a global decrease in miRNA levels [3]. This dysregulation of the miRNA can be linked to a particular tissue in human cancer because the expression patterns of miRNA appear to have tissue specificity. Another significant justification for using miRNA as a biomarker is that miRNA has an unusually high stability in formalin-fixed tissues, which means that the miRNA can be stored and extracted with minute degradation. This evidence led scientists to believe that miRNA may be exceptionally stable in plasma and serum as well [1].

In a study published in the Proceedings of the National Academy of Sciences, a laboratory in the Fred Hutchinson Cancer Research Center in Seattle, WA discovered that human plasma contains small RNAs of about 18-24 nucleotides each. This is congruent with the size of miRNA. Then they determined that miRNA was present in human plasma by creating an RNA cDNA library. In the library, of the 125 clones, 27 were found to be spiked-in size marker oligonucleotides, which are small nucleic acid polymers, or linker-linker dimers, which are larger nucleotides. Of the other 98 clones, 93% corresponded to known miRNAs, which provided direct evidence that a significant portion of 18-24 nucleotide-length RNAs present in human plasma are mature miRNAs.

The same laboratory also discovered that the miRNAs in the human plasma can be traced back to specific tissue by using TaqMan quantitative real-time PCR to measure miRNA-15b, miRNA-16, and miRNA-24 in plasma from three healthy individuals. All the miRNA tested for were readily found in the plasma of each healthy individual. Then the lab sought to discover the stability of the miRNA in the plasma by stressing it through subjecting it to eight cycles of freezing and thawing or incubating the plasma at room temperature for 24 hours. Subsequently, they measured the levels of the three miRNAs and found that the miRNAs were not significantly degraded. The laboratory in the Fred Hutchinson Cancer Research Center realized that serum is more readily available than plasma, so they tested the stability of miRNA compared to the plasma and found out that the stability in plasma and serum were strongly positively correlated.

Now that they found the baseline levels of expression of miRNA in healthy individuals, they had to find how miRNA expression is affected in cancer afflicted patients’ serum. The researchers in the Fred Hutchinson Cancer Research Center completed an experiment of detecting human prostate cancer from measurements of prostate cancer-expressed miRNAs in serum, which are miRNA-100, miRNA-125b, miRNA-141, miRNA-143, miRNA-205, and miRNA-296. They concluded that miRNA-141 expression is specifically elevated in prostate cancer in serum. The researchers extended this conclusion by another experiment that illustrated that miRNA-141 is expressed by several common human cancers [1]. The overall conclusion the researchers established that tumor-derived miRNAs can be detected in plasma or serum and serve as an effective circulating biomarker of common human cancer types.

If society knows that cancer can be found and treated easily, then people will worry less. The implications of miRNAs as biomarkers for cancer even extend to law. Since, miRNA can be used to diagnose cancer effectively, it means that there will be less false positives or false negatives, meaning that there will be substantially fewer malpractice lawsuits against oncologists. Lawsuits for oncologists are significant and devastating for their lives according to an oncologist on the board of directors of a medical malpractice insurance company, Patricia Legant, MD, PhD. In an article, she stated that a significant potential area of litigation for oncologists comes from a delay in the diagnosis of cancer [2]. The discovery of miRNA will monumentally decrease the delay in diagnosis of cancer because a blood test can be used to diagnose.

The implications of the conclusion for the research of miRNA are significant. When the use of miRNA as biomarkers enters the clinical field, the psychological effects on patients will be dramatic because the patients will endure less stress as a result of knowing which cancer is afflicting and whether it will be treatable. Also, they will not be subjected to as many invasive or painful tests. In addition, miRNA plays a role in tumor invasion and metastasis, which means that it can be used to provide a more specific and effective treatment [3]. The discovery of miRNA as a successful biomarker has even led the research into miRNAs as therapeutic targets because of its integration in cancer [3]. Along with the scientific aspects of miRNA, there are many economic aspects too. Using miRNA as a biomarker will save oncologists from doing many invasive and/or expensive tests to find out if a patient has cancer and what type of cancer because a blood test with a much a cheaper miRNA assay or electrophoresis can be used as a substitute. Another economic benefit to miRNA as a biomarker is that oncologists will be less likely to practice defensive medicine, which includes running unnecessary and often expensive tests to defend themselves against lawsuits, because miRNA is 97.6% accurate for sensitivity as a biomarker for cancer and 96.3% accurate as a biomarker for the classification of cancer [4]. Thus showing that the discovery of miRNA as a biomarker for cancer is successful because the accuracy is incredibly high, the hope for the patients’ is significant, the process of using miRNA is greatly feasible, and the cost effectiveness is monumental.

References

1. Mitchell, Patrick S. “Circulating microRNAs as stable blood-based markers for cancer   detection.” Proceedings of the National Academy of Sciences 105. 30 (2008), 10515, http://www.pnas.org/content/105/30/10513.full.pdf. (accessed September 25, 2010)
2.  Legant, Patricia. “Oncologists and Medical Malpractice.” Journal of Oncology Practice 2. 4  (2006), 164-169, http://jop.ascopubs.org/content/2/4/164.full#cited-by. (accessed October 8, 2010)
3.  “MicroRNA—implications for cancer.” National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151131/ (accessed October 8, 2010).

By Rohit Patil, George Washington University

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