Possible genetic flag for brain cancer

Defects in two IDH genes appear unique to certain brain tumors, although the genes’ role is unclear

Mutations in two genes, IDH1 and IDH2, might provide markers that enable doctors to discern malignant from benign brain tumors and catch some cancers early, scientists report in the Feb. 19 New England Journal of Medicine.

The study adds to a growing list of molecular clues that doctors may ultimately use to diagnosis and treat cancers, says study coauthor D. Williams Parsons, a pediatric oncologist and Howard Hughes Medical Institute investigator at Johns Hopkins University in Baltimore.

Doctors diagnose nearly 200,000 brain cancers each year in the United States. Most get their start elsewhere in the body and spread to the brain. But in about 22,000 of these patients, the cancer originates in the brain or central nervous system. These primary brain tumors are most often gliomas — clusters of tumor cells that derive from the brain’s glial cells. Gliomas vary in virulence from benign (grade 1) to fast-growing and rapidly lethal (grade 4).

The IDH genes are so-named because they encode an enzyme called isocitrate dehydrogenase. While the role of the enzyme is poorly understood, the mutations in IDH genes attracted interest after turning up last year in brain tumors but not in other cancer tissues. In the new study, the researchers tested samples of benign and cancerous primary brain tumors removed from 445 people and from tumors obtained from 494 others who had cancers of the colon, prostate, pancreas, breast, stomach, ovary or blood (leukemia).

No benign brain tumor cells harbored a mutation in the IDH genes, nor did any of the cancerous samples taken from elsewhere in the body.

But about 70 percent of low- to mid-range gliomas — grades 2 and 3 — had a mutated IDH gene, mainly IDH1. These malignancies account for thousands of cases of brain cancer each year, Parsons says. The mutation was rare in most grade 4 cancers unless they arose directly from lower-grade gliomas.

The finding suggests that these IDH mutations “play a unique role in the pathogenesis of gliomas,” says physician Craig Thompson of the University of Pennsylvania in Philadelphia, writing in the same NEJM issue. As such, determining the role of the genes and the enzymes they encode could elucidate a molecular target for brain cancer therapy, he says.

Meanwhile, the finding might have more immediate value in the clinic. After a surgeon removes a brain tumor or part of it, a pathologist analyzes the tissue. But it can be difficult to tell a benign tumor from a slow-growing grade 2 tumor, which is nonetheless cancerous. “A grade 2 tumor always progresses to a grade 3 and 4. It might take years,” Parsons says. Thus, the new finding might help pathologists catch more malignant tumors early, he says.

Ultimately, the IDH mutations may prove to be “gatekeeper genes“ for certain gliomas, says study coauthor Hai Yan, a cancer geneticist at Duke University Medical Center in Durham, N.C. Cancers get their start when genes mutate and change the cell’s behavior. Advanced cancers have so many such mutations they resist cure. But catching such defects early — right out of the gate — would simplify the target and improve the chance of stopping the cancer, Yan says.

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