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Study Identifies Metastasis-specific microRNA Signature in Colorectal Cancer

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NEW YORK (GenomeWeb) – Researchers from Baylor University and the National Cancer Institute have published new data suggesting that a signature of four microRNAs can be used to predict colorectal cancer (CRC) patients who will go on to develop metastatic disease.

The findings, which are currently being validated in samples from additional patients, may lead to the development of a test that oncologists can use to inform their decisions on which patients require aggressive chemotherapy after tumor removal and which do not.

CRC remains the second leading cause of cancer deaths globally, in part because of the high rate of metastatic disease — primarily in the liver — among patients and a lack of tools to identify early-stage and more treatable metastases.

When dealing with CRC patients with Stage I, II, or III disease — wherein a tumor is large but has not spread beyond nearby lymph nodes to distal tissues or organs — oncologists have no way to know which should receive aggressive treatment and which should not, a key consideration given the side effects and high costs of such therapies, Baylor researcher Ajay Goel, who led the newly published research, told GenomeWeb.

As such, there is a pressing need for metastatic-specific biomarkers that can help predict outcomes and guide follow-on treatments for patients at risk of advancing into Stage IV metastatic disease. Given his longstanding work in the miRNA field, as well as a growing body of data linking miRNAs to cancer, Goel set out to see if differential expression of small, non-coding RNAs could be used for such a purpose.

And while he conceded that he and his team are not the first to try to do so, he noted that their latest study, which appeared in the Journal of the National Cancer Institute, was unique in that it measured miRNA signatures in both primary CRC and metastatic liver tumors.

"Previous studies for discovering CRC metastasis-specific miRNAs had the potential limitation of analyzing unmatched pairs of primary tumors and [liver metastases] or lymph node metastases," according to the JNCI paper.

However, "analyzing [metastatic] tissue really tells you what molecular event led to escape of the tumor cells from the colon all the way to the liver," Goel said.

Such a study is particularly challenging because it typically takes years for CRC to metastasize, during which time a patient is likely to be treated by different physicians at different clinics. But by taking advantage of a network of collaborations in the US and Japan, Goel and his colleagues were able to obtain samples of primary CRC and matched liver metastasis tissue from about 75 patients.

By analyzing these samples, the researchers identified 23 that were differentially expressed between primary CRC tumors and liver metastases, of which five were quantitatively validated in primary CRC tissue. Four of these — let-7i, miR-10b, miR-221, and miR-320a — were downregulated in the metastatic tissue, and one — miR-885-5p — was upregulated.

Further examination showed that in primary CRC tissue, low let-7i expression and high miR-10b expression could independently predict distal metastasis.

The scientists also examined miRNA expression in serum, and found that high levels of miR-885-5p could independently predict prognosis and metastasis. Notably, this miRNA's expression in tissue had no predictive value.

The expression patterns of all the miRNAs were confirmed by in situ hybridization.

Despite the positive outcome of the study, Goel cautioned that "this is not the end of the story; this is just a good start. We are now in the process of continuing to validate this in a larger sample size," and exploring the possibility of improving the panel with additional miRNA markers.

Diagnosis

In addition to his work developing miRNA biomarkers for determining CRC metastasis risk, Goel and his lab are also continuing efforts to create a serum-based miRNA assay that can be used to diagnose the disease.

Currently, CRC diagnosis is performed with a colonoscopy. However, the invasive nature of the test results in poor patient compliance, with about half of people recommended for screening not following through.

Additionally, because a colonoscopy is an expensive procedure and only a small fraction of people screened will have CRC, it is especially burdensome for the healthcare system, Goel said. And because screening guidelines call for a colonoscopy once every 10 years, there is ample time for an individual who has received a clean bill of health to develop CRC.

A blood-based test, he added, could address these issues, acting as a prescreen that could be implemented on a yearly basis along with routine blood tests to identify which individuals should undergo colonoscopy and which do not need to.

In 2013, he and collaborators reported the results of a study of serum samples from CRC patients, as well as individuals with benign tumors and controls, that found expression of miR-21 was statistically significantly associated with tumor size, distant metastasis, and poor survival in CRC patients. The miRNA also proved to be an independent prognostic marker for CRC.

While encouraging, the data are preliminary. Moreover, only about 80 percent of CRC patients were correctly differentiated from healthy controls, Goel said. While false positives would only result in people receiving additional unnecessary screening, failing to identify patients with CRC would be far more serious.

"We're still missing 10 to 20 percent of people, and we can't do that," he said.

With the help of a grant from the NCI, Goel and his colleagues are preparing to further validate miR-21 as a biomarker for early CRC diagnosis and identify additional serum miRNAs that could be used to boost its clinical utility.

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