Investigators Pinpoint Two Genes as Targets for Treatment and Prognostic Markers for Glioma

Researchers from Duke University Medical Center and Johns Hopkins University report finding mutations in two genes that could be used as therapeutic targets for malignant glioma as well as prognostic markers. The genes under study were isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2).

Since they found this genetic mutation in several different stages of glioma development, the team suggests that the IDH mutations are among the earliest genetic changes that start glioma progression. “The mutations appear to occur very early in the progression of these cancers, perhaps at the stem cell level,” says Bert Vogelstein, M.D., co-director of the Ludwig Center at Johns Hopkins.

Additionally, since they could not locate IDH1 mutation in pilocytic astrocytomas, they believe that this particular type of brain tumors arises through a different mechanism.

Regarding the therapeutic potential of the findings, Hai Yan, M.D., Ph.D., lead author, an assistant professor in the Duke department of pathology, says, “The fact that the defective genes code for metabolic enzymes found only in malignant glioma and not in normal tissue could make the gene products therapeutic targets.”

The mutations could also help distinguish between primary and secondary glioblastoma multiforme (GBM). The group’s studies indicate that patients who possess the IDH1 or IDH2 mutation survive longer than patients without these mutations.

The scientists looked for IDH1 and IDH2 gene alterations in material taken from 500 brain tumors and 500 noncentral nervous system cancers. They located IDH1 mutations in more than 70 % of astrocytomas and olidgodendrogliomas (WHO grade II and III) as well as in secondary GBMs (WHO grade IV). Those without the IDH1 mutation had similar mutations in the closely related IDH2 gene.

The mutations decreased IDH enzymatic activity, the scientists report. They thus believe that IDH mutations are likely important in initiating malignant gliomas, but it is not known yet how they contribute to glioma development.

The researchers also looked at survival time and found that the median survival for glioblastoma patients with mutations in either IDH1 or IDH2 was 31 months versus 15 months for those lacking the mutations. Anaplastic astrocytoma patients carrying the mutations were found to have a median survival of 65 months as compared with 20 months for those who did not.

The scientists say that they could not compare survival data in oligodendroglioma patients, because there were too few tumors that did not carry the mutations.

The findings are published in the February 19 issue of the New England Journal of Medicine.

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