Researchers at the Johns Hopkins Oncology Center have uncovered a genetic alteration that appears to predict how individuals with an aggressive type of brain cancer will respond to chemotherapy.

The discovery, published in the Nov. 9 issue of the New England Journal of Medicine, emerged from analysis of tumor samples from 47 patients with glioma, all of whom received standard treatment with the drug carmustine. In 19 of the patients, the methyl-guanine-DNA methyltransferase (MGMT) gene appeared in a chemically altered form and 12 of these 19 had significantly better responses to chemotherapy, including regression of the tumor and increased long-term survival. This is compared with one patient of the 28 with unaltered MGMT genes who responded to the chemotherapy. Patients with altered MGMT genes lived an average of 13 months longer than the other patients.

The MGMT gene is altered through a biochemical process known as methylation. The Hopkins scientists speculate that the normal, so-called unmethylated MGMT genes support repair of DNA damage, including damage caused by chemotherapy drugs, and therefore inhibit effectiveness of the drug. When the gene is altered or methylated, however, repair activity is blocked, allowing the anticancer drugs to attack the cancer cells unchecked.

The researchers currently are investigating agents that will block the MGMT gene and increase tumor sensitivity to carmustine. "The ability to detect the methylated form of the MGMT gene may provide a new way of preselecting some cancer therapy based on a tumoršs chemical profile," says James G. Herman, assistant professor of oncology and principal investigator of the study.

"The most exciting aspect of this research is that we can begin applying it to therapy right away," says Manel Esteller, research fellow at the Oncology Center and first author of the paper. "We donšt have to wait for new drugs to be developed; rather we can begin more effectively tailoring the drugs we are using today," Esteller says.

"We want to caution," Herman adds, "that testing for MGMT gene methylation in brain tumors is not yet widely available." Virco Lab Inc. (Great Britain) has licensed the technology from Hopkins and could have a commercial test available as early as 2001.

Methylation has long been known to help regulate the expression of proteins made by genes by adding chemical molecules to genetic on/off switches, technically called promoter regions. When the gene is unmethylated, the gene turns on. When it is methylated, the gene turns off. Its role in cancer also has been well-defined, with similar methylation patterns playing a role in colon cancer, lung cancer, lymphoma, and head and neck cancers.

Thirteen thousand people in the United States die each year from brain cancer, and more than 16,000 are diagnosed annually with the disease. Though rare, brain cancers are among the deadliest and most debilitating types of malignancies. Patients frequently die within months of diagnosis.

The research was funded by the National Cancer Institute.

In addition to Herman and Esteller, the researchers were Steven N. Goodman and Stephen B. Baylin, from Hopkins, and Jesus Garcia-Foncillas, Esther Andion, Oscar F. Hidalgo and Vicente Vanaclocha, from the University Hospital of Navarre, Pamplona, Spain.