Tumor-Squelching Gene Nabbed at Last

Researchers have finally been able to make the charges stick against a long-suspected tumor suppressor gene. The gene, called NF1, was pinpointed in 1990 as the culprit in neurofibromatosis (NF), a disfiguring and potentially deadly disease that affects one in 3500 people.

In tomorrow's issue of The New England Journal of Medicine, researchers from the University of California, San Francisco, and Roche Biomedical Laboratories report convincing evidence that the NF1 gene acts as a tumor suppressor in human cancer. Such genes help regulate cell division, and when they are missing or inactivated by mutations, cell division runs amok, resulting in tumors. The finding suggests that therapies under development that target the cell division pathway may hold great promise for NF1 patients, who develop numerous noncancerous tumors and have a highly elevated risk for several kinds of cancer.

Scientists already had reams of circumstantial evidence that NF1 was a tumor suppressor. The disease itself, with its multiple tumors, suggests the handiwork of such a gene gone awry. And within a few months of NF1's discovery, researchers had found that its sequence was remarkably similar to a gene called GAP, which was known to regulate the system of signals that tells a cell to divide. Data from mice, too, suggested that the gene was necessary to prevent tumor development. But it has proven difficult to collect the firm evidence needed to confirm the tumor-suppressor role.

The best way to prove that a gene is a tumor suppressor is to show that the gene is functioning properly in normal cells, but is missing or inactive in tumor cells. That has been difficult to prove for NF1, because the huge gene could potentially contain thousands of mutations that would render it inactive, and it is impossible to screen for all of them. But a recently developed trick for examining the protein product of the gene enabled Kevin Shannon, a pediatric hematologist and oncologist at the University of California, San Francisco, and his colleagues to collect the incriminating evidence. They examined tissue samples from 18 children with NF who also developed leukemia. In eight of the patients, normal cells showed one mutated NF1 gene and one normal gene, while cancerous cells had only the mutated form. "Compelling evidence," says Shannon, that the NF1 gene is in fact the culprit in the cancers.

Other researchers applaud the work. "This is the best example that NF1 is a tumor suppressor," says David Viskochil, a geneticist at the University of Utah, although he cautions that the case is not yet closed: There still could be other genes that play a role in NF tumor development. Nevertheless, he says, the finding suggests that drugs that block the cell-division pathway will be an effective treatment for NF-related leukemia and potentially for other disease complications.