February 24, 2009 — The diagnosis and treatment planning of gliomas are likely to improve as a result of new findings that link 2 gene mutations to certain types of the brain tumors.
Two gene mutations, of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2), occur in a "vast majority" of grade II and III gliomas and secondary glioblastomas, according to researchers from Johns Hopkins and Duke universities.
The new findings are reported in the February 19 issue of the New England Journal of Medicine.
The ability to test for these mutations will allow pathologists and clinicians to be more precise in the diagnosis of gliomas, said coauthor D. William Parsons, MD, PhD, visiting professor in pediatric oncology at the Johns Hopkins Kimmel Cancer Center, in Baltimore, Maryland, and assistant professor at Baylor College of Medicine, in Houston, Texas.
"Let's say I have a patient with a brain tumor. The pathologist might say, 'It's a glioma, but it's uncertain if it's grade I or II.' Now, the pathologist can add this test and it will be an adjunct to the current histopathology and other techniques for the diagnosis of gliomas," Dr. Parsons told Medscape Oncology.
Decisions about the "aggressiveness of therapy" are shaped by the classification and grading of the tumor, he added.
Dr. Parsons likened the significance of IDH1 and IDH2 mutations in gliomas to epidermal growth factor (EGFR) mutations in lung cancer in terms of classifying patients.
"We are moving from a crude categorization and classification via histopathology to a more precise molecular classification in oncology [in general]," observed Dr. Parsons. Gliomas with IDH1/IDH2 mutations make up a clinically and biologically distinct subgroup of brain cancers, he added.
These gliomas are also good candidates for targeted therapies in the future, he declared. "You can imagine designing an inhibitor for this, because of the specific nature of these gliomas," he said, referring to the specific enzymatic activity that is altered by the mutations.
"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," adds study lead author Hai Yan, MD, PhD, assistant professor of pathology at Duke University Medical Center, in Durham, North Carolina, in a statement.
Testing for the mutations will not entail "a fancy, expensive commercial test," noted Dr. Parsons, explaining that academic medical centers have the technology (polymerase-chain-reaction assay) to test for the mutations and will probably refine their own techniques.
Mutations Linked to Progression to High-Grade Tumor
Gliomas are the most common type of primary brain tumors and are classified according to criteria established by the World Health Organization. Grade I gliomas are usually considered benign, whereas grade II (astrocytomas) and III (oligodendrogliomas) are invasive, progress to higher grade lesions (including grade IV, secondary glioblastomas), and have poor outcomes, the authors explain.
In the new study, the investigators looked for IDH1 and IDH2 gene alterations, which had been previously linked to gliomas in a smaller analysis, in brain tissue and blood samples taken from 445 brain tumors and 494 non–central nervous system cancers. They found changes in the IDH1 gene in more than 70% of astrocytomas, oligodendrogliomas, and secondary glioblastomas. Some of the brain cancers that did not have alterations in IDH1 had equivalent mutations in another closely related gene, IDH2.
The findings "implicate" the 2 gene mutations in the "pathogenesis of malignant gliomas," the authors write.
Grade II (astrocytomas) and III (oligodendrogliomas) often carry IDH mutations but not other genetic mutations that are detectable relatively early during the progression of gliomas, they explain. "This finding suggests that IDH mutations occur early in the development of a glioma from a stem cell that can give rise to both astrocytes and oligodendrocytes," they write. Also, they note that the mutations were not identified in any grade I astrocytomas, the usually benign gliomas.
"The IDH mutations are remarkably specific to the 2 subtypes of gliomas [astrocytomas and oligodendrogliomas]," summarized Dr. Parsons.
Longer Survival with Mutations
Patients with a glioma that carried an IDH1 or IDH2 mutation had a significantly longer survival compared with patients with the wild-type IDH gene. The investigators said that further analysis was required to specify why the difference occurs. However, finding is potentially helpful in the clinic. "The IDH mutation could serve as a biomarker that would help single out individuals who are likely to have better outcomes and receive different treatment," says Dr. Yan.
In the study, glioblastoma patients carrying the mutations had a median overall survival of 31 months vs 15 months for the wild-type carriers (P = .002). Astrocytoma (anaplastic variety) patients carrying the mutations had a median survival of 65 months as compared with 20 months for those who did not (P = .001).
Differential survival analysis could not be performed in patients with diffuse astrocytomas, oligodendrogliomas, or anaplastic oligodendrogliomas, because there were few tumors that did not carry the IDH mutations.
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