"Jumping" DNA: A Tool for Finding Cancer Genes
Researchers have developed a new method of inducing cancer in mice and then rapidly identifying the genes involved. The mice are engineered to carry bits of DNA called transposons that, in the presence of a particular protein, jump randomly around the chromosomes of mouse cells, occasionally landing in genes and causing mutations.
As genetic mutations accumulate, the mice develop aggressive tumors and die. Researchers can pinpoint which genes were mutated by tracking molecular "tags" that mark where the transposons inserted themselves. Commonly mutated genes in mouse tumors may be versions of cancer genes in people.
"We think this is a powerful way to identify cancer genes for many different cancers," says Dr. Neal Copeland of the Mouse Cancer Genetics Program in the National Cancer Institute's (NCI's) Center for Cancer Research. "A number of the cancer genes we have found so far in the mice are known cancer genes in humans."
The researchers have also identified some potentially novel cancer genes. One of the new method's appealing features is that no prior knowledge about the genetics of a tumor is required to search for genes.
The project was started by Drs. David Largaespada and Adam Dupuy at the University of Minnesota in Minneapolis in 1997. A few years ago, Dr. Dupuy brought the transposon technology to NCI, where he has been working with Drs. Copeland and Nancy Jenkins.
The Minnesota and NCI groups collaborated while testing the method in different types of mice. Regardless of genetic background, the mice all died within 120 days, and some developed multiple tumors, according to findings in the July 14 Nature.
Dr. Largaespada began the project just as colleagues at the University of Minnesota had created a modified transposon using a version from salmon. Like almost all DNA transposons in vertebrates, it had not functioned for millions of years, but the researchers eliminated genetic mutations that had rendered it immobile, causing an "awakening."
Named Sleeping Beauty, the transposon has been used to induce mutations in the sperm and eggs of mice. But the transposon was not active enough to cause tumors, so the challenge was to increase the frequency of movement from one chromosomal location to another.
The researchers succeeded, and the new Sleeping Beauty transposon system can cause tumors in a variety of tissues throughout the lifetime of a mouse, providing another tool for finding cancer genes and potential leads for treatments.
"In some mice, clusters of gene mutations accumulate over time, and you begin to see a tumor's genetic 'fingerprint,'" says Dr. Largaespada. "This is important because the most effective cancer treatments may be combinations of drugs that attack each mutant gene product."
Dr. Dupuy recently modified the system so that Sleeping Beauty can be made to jump in specific tissues rather than around the whole body. The researchers are developing mice that can be used to investigate breast, colon, and prostate cancer in people.
The mice could also help researchers sift through the avalanche of mutations routinely identified in human tumors. For example, the proposed cancer genome project, which is in a pilot project planning phase, will need tools for identifying mutations that actually contribute to the disease, as opposed to just being present in tumors.
By Edward R. Winstead