Cancer switch: good gene is shut off in various malignancies.

A gene called Reprimo is shut down in several cancers but rarely in healthy cells, a new study shows. This finding suggests that the gene's normal action would somehow inhibit these cancers. What's more, Reprimo is stalled in some precancerous growths, indicating that its silencing might occur in the early stages of cancer, says Adi F. Gazdar, a pathologist at the University of Texas-Southwestern Medical Center in Dallas.

Reprimo is poised to take its place on the growing list of genes that normally keep cell growth in cheek but fail in cancer. Identifying such cancer-suppressor genes has already improved cancer screening and could lead to new therapies, Gazdar says.

His team reports that a cell can stifle Reprimo activity by attaching chemical methyl groups to a DNA on-off switch, called a promoter, that's near the gene. Scientists have previously implicated this process, called methylation, in the shutdown of other genes associated with cancer suppression (SN: 6/24/00, p. 407).

Previous research on Reprimo, which sits on human chromosome 2, had shown that the gene is inactive in some pancreatic and lung tumors. When Gazdar's team tested 645 tumor samples representing 16 kinds of cancer, the gene's switch was methylated in most samples of lymphoma and stomach cancer, colorectal cancer, and gallbladder cancer. Reprimo was also methylated in 40 percent of esophageal cancer samples tested and in one-third of leukemia and breast cancer samples. In contrast, healthy tissues rarely showed a methylated Reprimo gene, the researchers report in the July 1 International Journal of Cancer.

To confirm that methylation was responsible for silencing Reprimo in the cancerous cells, the researchers treated some of the cells with a demethylating agent. That treatment reactivated Reprimo.

"This demonstrates that [methylation of Reprimo] is a common alteration in many different tumors," says medical oncologist James Herman of the Johns Hopkins Medical Institutions in Baltimore. "This work complements other tumor-suppressor research .... It adds another potentially important gene to that group."

Not all cancers demonstrate Reprimo silencing. Cells taken from cancers of the ovaries, brain, bladder, or cervix or from any childhood tumor showed little methylation of Reprimo, the researchers found.

On the other hand, methylated Reprimo showed up in one-fourth of all colon polyps tested. Some such polyps are precancerous, and doctors routinely remove all polyps discovered in patients' colons.

The findings suggest that aberrant methylation of the Reprimo promoter is among the earliest events in the origin of some cancers, Gazdar says. For this reason, detecting methylation of Reprimo could tip off doctors to the onset of many cancers.

Some demethylating agents have knocked out cancer in laboratory animals, and at least one such compound is being tested in people who have a blood cancer.

The precise role of the protein encoded by Reprimo remains murky, but Gazdar and his colleagues uncovered evidence that it teams up with the cancer-suppressing protein p53. That protein plays a pivotal role in derailing abnormal replication of cells. If that process fails, p53 can orchestrate cell suicide, Herman says.

"Once we understand the [biochemical] pathways involved in cancer biology, we'll have a handle on how to treat these cancers" Gazdar says.