MicroRNA markers show staying power

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For example, he points out, in lung cancer a microRNA might act as an oncogene in humans but not in mice. He reported this shifting nature of micro-RNAs in a paper that compared the phenomenon to Robert Louis Stevenson’s Dr. Jekyll and Mr. Hyde (Fabbri M, et al. Regulatory mechanisms of micro-RNAs involvement in cancer: the strange case of Dr. Jekyll and Mr. Hyde. Expert Opin Biol Ther. 2007;7(7): 1009–1019).

In 2007, Dr. Fabbri published a paper in which it was observed that one cluster of two micro-RNAs is able to affect expression of 14 percent of the genome. “So of course you cannot think that in this 14 percent of the genome there are only oncogenes or only tumor suppressor genes. There’s a mixture.” He compares the phenomenon to that of forces in physics. “If you have different forces applying in different directions, then you take the direction which is the result of all the forces applied. I like to see microRNAs in this way.”

Dr. Fabbri believes researchers are very close to understanding the activity of microRNAs. “The signatures of dysregulated microRNAs have been basically described since 2004. And every day there are more and more papers showing targets and validating the targets of specific microRNAs.” Now, for example, if you give a pathologist a tumor and he or she doesn’t know which tumor it is, “just by looking at which micro-RNAs are down- or upregulated, it is possible to guess with a good amount of success the tissue of origin.”

This is a great breakthrough, he says. “As we speak, there are still eight or 10 percent of cancers of unknown primary origin that are metastasized, and the clinician is not able to see the primary tumor. So this is very important if we can guess the tumor of origin from the microRNA expression profile, because you can give your patient a better treatment with fewer side effects.”

The specific signatures of microRNAs also have prognostic implications for risk stratification, he adds. “If you take patients who already have a clear diagnosis—for example, chronic lymphocytic leukemia patients—then one of the biggest challenges for clinicians is that you don’t really know what the outcome of that disease is. It can be indolent or aggressive, but clinicians don’t have good tools to guess.” In a paper he coauthored, Dr. Fabbri showed that microRNA expression can help with this identification, which allows a clinician to treat more aggressive disease types more quickly (Calin GA, et al. A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005;353:1793–1801). He envisions the use of microRNAs in conjunction with current chemotherapy and radiotherapy within five or six years.

Dysregulation of some micro-RNAs seems to occur early in a disease’s natural history. “You don’t have to wait for stage four lung cancer to see certain microRNAs popping up, so they are really good diagnostic biomarkers,” Dr. Fabbri says. “They’re also really good, after a patient has been operated on, at predicting recurrence of the disease when the disease is not even detectable yet. And they can be identified not only in the blood but in all human biological specimens you can possibly imagine, depending on the cancer—for example, saliva, in the case of head and neck cancer.”

Dr. Fabbri says it’s important to understand that microRNAs do more than just silence genes. “So far, people have focused on micro-RNAs as an obstacle to expression. They bind to the target gene and prevent it from becoming a protein, so they are excellent regulators of gene expression, but they don’t just do that. There is much more to their mechanism of action.”

He blames traditional dogma of molecular biology for the initial belief that microRNAs were “junk DNA.”

“A gene is a piece of DNA transcribed into messenger RNA which is translated into a protein. People just focused on this DNA/RNA/protein link, and if a piece of DNA was not doing this, it was considered not helpful. But cells do not spend a single molecule of their energy to do something that is not helpful or not doing anything. Fortunately, people realized at some point that 98 percent of our DNA does not encode for protein. And this whole group of what used to be called junk—microRNA is only a small fraction of it—is now called ‘noncoding DNA.’”

However, not all researchers are as sanguine about microRNAs’ prospects in the short term. Federico Monzon, MD, a molecular pathologist at Invitae Genetics Laboratory in San Francisco, studied expression of microRNAs in different types of renal tumors when he was an assistant professor of pathology at Houston Methodist Hospital. “We explored micro-RNAs as tools for renal tumor subtype classification because they are amenable to developing diagnostic assays that are easily implemented in the laboratory.”

Now in industry, where he focuses on genetic testing based on next-generation sequencing, Dr. Monzon does believe microRNA shows promise. “There’s a good amount of literature describing specific microRNA profiles associated with tumors. But these profiles have not been developed as robust clinical tools yet.”

“My skepticism is mostly that we don’t have strong links with outcomes. We know a lot about how specific microRNAs might be increased in one tumor or another, but we don’t yet have a validated way to use that information to make clinical decisions, and that’s where the gap is.”

Of therapeutic applications, he says: “We have associations, but we don’t know how to modulate microRNAs, so if we discover that an aggressive tumor has a specific microRNA profile, it doesn’t necessarily mean there is something we can do for the patient. If you have a specific profile that could identify who responds to traditional therapy, that would be useful, and it’s still possible. We just need to find out with the appropriate research.”

Dr. Tsongalis, of Dartmouth, would agree that microRNA may not pan out with every application now being researched. But, he says, “I’m not sure people have really picked up on the impact microRNA could have, diagnostically.  There will be certain areas where it will end up as the biomarker of choice. It’s just a matter of people getting used to the concept and being able to relate microRNAs back to what the clinical question is. And once that happens, I think there are a number of applications that this will be routine for.”

MicroRNAs are still evolving, he emphasizes. “But we’re moving toward clinical use very quickly. The data is supporting a lot of different applications on the clinical side, so the naysayers, I think, will be paying a little bit more attention. Because this is not your average biomarker.”

Anne Paxton is a writer in Seattle.