Survey of Tumors Reveals Second Gene "Signature"
New research suggests that a recently discovered class of genes called microRNAs could potentially be used broadly to diagnose and classify tumors, including those of unknown origin.
During the last 5 years, researchers have found more than 200 microRNAs in humans. These small molecules - about 25 units of genetic code in length - are thought to regulate the activity of genes during development and may do the same for some genes involved in cancer.
To determine whether profiling microRNA gene activity would yield useful information, researchers in Boston surveyed the activity of 217 microRNA genes in a diverse collection of human tumors. The microRNA genes were "surprisingly informative," and the researchers found signature patterns of activity associated with different tumors, they report in the June 8 Nature.
"In terms of classifying cancers, these microRNA genes appear to pack a lot of punch," says Dr. Todd Golub of the Dana-Farber Cancer Institute and the Broad Institute of Massachusetts Institute of Technology and Harvard University.
The microRNA genes were particularly useful in diagnosing tumors that no longer resembled the tissues that originally gave rise to them. In fact, just 200 microRNA genes were more informative than 16,000 conventional genes that were profiled for comparison. If a proposed Human Cancer Genome Project goes forward, Dr. Golub notes, it would make sense to include information about microRNA genes "because the profiling can be done at low cost and may be informative."
Some researchers are already using microRNA gene signatures experimentally to distinguish between patients who have very different forms of the same cancer. "We have a microRNA gene signature for chronic lymphocytic leukemia that tells us whether a patient will likely need aggressive treatment or not," says Dr. Carlo Croce of the Ohio State University Comprehensive Cancer Center, who is preparing a paper on the subject.
Dr. Croce and his colleagues reported last year that 50 percent of the known microRNA genes reside in chromosomal regions that are either unstable or associated with cancer. The challenge now is to identify the genes that are regulated by microRNAs - and to figure out how microRNA genes themselves are regulated.
Two other studies in the same issue of Nature explore these questions with regard to the gene Myc, which is implicated in many cancers and activates a cluster of microRNA genes on chromosome 13.
In one study, led by Dr. Gregory Hannon of Cold Spring Harbor Laboratory, this cluster of microRNAs accelerated the growth of tumors when transplanted into mice with overactive Myc genes. In the other study, two microRNAs from the same cluster were shown to alter levels of a protein called E2F1 that interacts with Myc. "We have just begun to scratch the surface," says Dr. Joshua Mendell of Johns Hopkins University School of Medicine, who led the E2F1 research. "Hundreds of genes are probably regulated by this cluster of microRNAs, and we need to characterize those relationships."
One such relationship involves the cancer-promoting gene RAS and a microRNA called let-7 that was recently found to regulate RAS. As it turns out, some lung tumors are missing let-7 and this loss may allow RAS to be overactive, researchers from Yale University reported in March. "We believe let-7 is a tumor suppressor gene in lung cancer, and that the loss of let-7 in some people contributes to the cancer," says Dr. Frank Slack, who led the study.
Dr. Slack predicts that more than 1,000 human microRNAs will eventually be found. "This is turning out to be a large class of molecules, and people are starting to appreciate them for the important regulators that they are," he says.
By Edward R. Winstead