Gene Silencer Linked to Cancer

31 January 2000 5:00 pm

Radiation or toxic chemicals can unleash cancer by destroying or damaging the genes that control cell growth. Now it seems that these critical checkpoints are vulnerable to another kind of genetic mishap: overzealous activity by a chemical gag order called methylation. According to a report in the February issue of Nature Genetics, the DNA in cancer cells can be methylated up to 10% more than in normal cells. The finding suggests a way for cancer gene hunters to narrow the search for their quarry.

Methylation seems to be a way for cells to turn off genes that are no longer needed, such as those that guide development. To decommission a gene, a methyl molecule is strapped onto a cytosine, one of the four building blocks of DNA; this addition somehow prevents enzymes from reading the gene. The worry is that if the wrong gene is silenced, methylation could short-circuit the production of vital tumor suppressor proteins or other molecules involved in regulating cell growth, says Joseph Costello, a cancer biologist at the University of California, San Francisco. For instance, the gene for the estrogen receptor is silenced in some breast cancers.

To find out how widespread methylation is in cancerous cells, Costello, Christoph Plass from Ohio State University in Columbus, and their colleagues studied methylation in DNA from 98 people, each of whom had one of seven kinds of cancer, including breast, neck, and brain cancer. Working with Webster Cavenee of the University of California, San Diego, they homed in specifically on stretches of DNA called CpG islands, which contain lots of cytosine and are potential methylation targets. After evaluating some 1200 CpG islands, the researchers estimate that the DNA in cancer cells had on average about 600 more methyl groups attached than DNA in normal cells had. That insight "has given us evidence for the importance of these events in tumors for which we don't have a whole lot of explanation from the genetics," Costello points out.

Moreover, they found, the seven cancers each had a unique distribution of methyl molecules, suggesting that methylation plays a different role in each cancer. "This tumor specificity is an important new finding," because it points to methylation as a player in some types of cancer, says Jean-Pierre Issa, an oncologist at the M. D. Anderson Cancer Center in Houston. The next step, he says, will be to find out what triggers the excessive methylation and how it sends cell growth spiraling out of control.

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