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Warning Sign: Genetic fragments tag cancer severity

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2:49pm, January 30, 2008
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A tiny piece of RNA can spell big trouble for some colon cancer patients.

Colon cancer patients who have high levels of a microRNA called miR-21 in their tumors don't respond well to standard chemotherapy and have poor prognoses, a new study shows.

MicroRNAs are short pieces of genetic material that help regulate the production of proteins from the recipes encoded in genes. MicroRNAs latch on to protein-coding messages, usually disrupting protein production. About 5 years ago, researchers discovered that disturbances in microRNA levels are associated with cancer.

Curtis Harris of the National Cancer Institute in Bethesda, Md., and his colleagues tested tumors from 84 Maryland residents with colon cancer. Levels of 26 microRNAs were on average higher in the tumors than in healthy tissues from the patients, while 11 microRNAs were produced at lower levels in the tumors. Patients with the highest levels of five microRNAs—miR-20a, miR-21, miR-106a, miR-181b, and miR-203—had poor survival rates, the researchers report in the Jan. 30 Journal of the American Medical Association.

The researchers singled out miR-21 for further study because it is also elevated in several other types of cancer, Harris says. Obtaining miR-21 data from 113 colon cancer patients from Hong Kong, the researchers confirmed the link to survival rates. In the two patient groups together, more than 60 percent of people with stage III tumors who underwent chemotherapy survived for 5 years if they had low levels of miR-21. Fewer than 20 percent of such people with the highest levels of miR-21 were living 5 years later, despite chemotherapy.

This study is the first to link a microRNA with how well patients do in treatment, comments developmental biologist Frank Slack of Yale University.

"I find this paper very exciting," he says. "I think it gives hope to millions of colon cancer sufferers because it means that, in the future, physicians might be able to read out their miR-21 levels and find out how well they'll do."

The molecule is the most common microRNA associated with cancer, he adds. It is elevated in 16 types of tumors.

The researchers don't yet know whether miR-21 can cause cancer on its own. Previous studies have shown that miR-21 interrupts the activity of two tumor suppressor genes, PTEN (for phosphatase and tensin homolog) and TPM1 (tropomyosin 1). It also knocks down levels of B-cell lymphoma 2 (Bcl-2), a protein that helps fend off cell death. MicroRNAs regulate many genes, and miR-21 may have multiple targets in pathways that control cell growth and death.

Colon cancer cells have problems besides elevated levels of the microRNA, Slack says. Tumor cells also carry mutations in protein-coding genes and have other abnormalities.

"What's happening here is that miR-21 is cooperating with other mutations in the cell," he says.

miR-21 may also work with other microRNAs. Levels of three others found in the study, miR-20a, miR-106a, and miR-181b, are elevated in other cancers, particularly leukemia.

MicroRNAs will be used for diagnosis and prognosis of cancer, and possibly treatment, within a decade, Harris predicts.

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