'MicroRNA' Predicts Liver Cancer Outcomes

'MicroRNA' Predicts Liver Cancer Outcomes
By Michael Smith, North American Correspondent, MedPage Today
Published: October 07, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
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Action Points

* Explain to interested patients that liver cancer, which usually has poor outcomes, has few therapeutic options, and tools are needed to determine which patients will respond to treatment.


* Note that this study found that a microRNA can predict how long patients will live and who will respond to treatment with interferon alfa.

A small segment of genetic material -- a so-called "microRNA" -- predicts survival and response to adjuvant interferon treatment in patients with hepatocellular carcinoma, researchers said.

In a cohort study, patients with low expression of the microRNA miR-26 in their tumor had significantly shorter survival (at P=0.02) than those with higher expression, according to Xin Wei Wang, PhD, of the National Cancer Institute, and colleagues.

On the other hand, those same patients were more likely to respond to treatment with interferon alfa, Wang and colleagues reported in the Oct. 8 issue of the New England Journal of Medicine.

Hepatocellular carcinoma, whose incidence in rising in the U.S., usually has "dismal outcomes," the researchers said, and there is a need for molecular tools that can help determine treatment and prognosis.

In general, more men than women get the disease -- by a factor of up to six, depending on ethnic group -- Wang and colleagues noted, which suggests that host and tumor factors may differ between the sexes.

Indeed, women who get liver cancer tend to live longer than men with the disease, they said, although the reasons for the disparity aren't clear.

To help clarify the issue, the researchers analyzed three cohorts of patients with liver cancer -- an initial group of 241 whose tumors were analyzed for microRNA expression patterns, and two groups, totaling 214, who had taken part in controlled clinical trials of interferon alfa.

MicroRNAs are small segments of noncoding ribonucleic acid that bind to messenger RNA and interfere with or silence its translation into protein, essentially regulating gene expression.

In this study, analysis found that members of the miR-26 microRNA family -- there are three in humans, miR-26a, a-1, and b -- were significantly more highly expressed in nontumor liver tissue in women than in men (at P=0.01 and P=0.001, depending on which cohort was tested).

The researchers defined low miR-26 expression in a tumor as being below the median of all those that were analyzed and hypothesized they would be biologically distinct.

Indeed, in patients with low tumor expression of miR-26, there was a significant difference (at P<0.001) between levels of the microRNA in tumor and nontumor tissue -- a difference that was not seen in patients with high tumor expression of miR-26.

Also, analysis showed a distinct pattern of gene expression associated with low tumor miR-26 -- signaling pathways between nuclear factor κB and interleukin-6 that might play a role in tumor development were preferentially activated.

In the two cohorts from the clinical trials of interferon alfa, the researchers found that:

* Low expression of miR-26 was associated with significantly lower overall survival at 72 months compared with controls, at P=0.01 and P=0.02, respectively.
* Low expression of miR-26 was associated with significantly better response to interferon alfa compared with controls, at P=0.003 and P=0.03, respectively.
* Patients with high expression of miR-26 did not respond significantly better than controls in either cohort.

The results suggest that miR-26 is a tumor suppressor, whose inactivation in tumor tissue contributes to a more aggressive form of the disease in men, Wang and colleagues said.

The research took place in an ethnically Chinese population, a large majority of which had hepatitis B, and the researchers cautioned that the findings of the study need to be replicated in other groups.

The study illustrates the potential value of microRNAs in cancer prognosis, according to Judy Lieberman, MD, PhD, of Harvard Medical School.

MicroRNAs "play an increasingly recognized important role when things go awry in cancer," she said in an accompanying editorial, and -- as in this study -- may be markers than can be used to predict the outcomes of therapy.

They may also play a direct role in therapy, she said, citing a recent animal study in which investigators saw liver tumors regress in mice injected with an adenovirus engineered to express miR-26a.

The study was supported by the National Cancer Institute.

Wang reported no conflicts.

Lieberman reported financial links with Alnylam, Cequent, Baxter, Asuragen, Genentech, Merck, Wyeth, Pfizer, and MedImmune, and GlaxoSmithKline. She also reported holding a patent and being named on patent applications for delivery of small interfering RNA molecules and the treatment of viral infections.

Primary source: New England Journal of Medicine
Source reference:
Ji J, et al "MicroRNA expression, survival, and response to interferon in liver cancer" N Engl J Med 2009; 361: 1437-47.

Additional source: New England Journal of Medicine
Source reference:
Lieberman J "Micromanaging cancer" N Engl J Med 2009; 361: 1500-01.