Mutations Make Some Brain Tumors Less Deadly

Cancer researchers have identified two genes that are mutated in some types of brain cancer and may be both targets for chemotherapy and useful as diagnostic biomarkers.

Investigators at Duke University (Durham, NC, USA) studied primary and secondary glioblastoma multiforme (GBM), two subtypes of especially deadly malignant brain tumors. Their work was based on a recent genome wide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) that revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). In the clinical setting, it was known that patients that had a mutation of the genes, isocitrate dehydrogenase 1, gene 1 and 2 (IDH1 and IDH2), had a longer survival time than those with the wild type form of these genes.

The investigators determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes.

Results published in the February 19, 2009, issue of the New England Journal of Medicine pointed to mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein.

"Malignant glioma appears to be two diseases, one that involves IDH mutations and one that does not," explained first author Dr. Hai Yan, assistant professor of pathology at Duke University. "As a cancer culprit gene, IDH mutations do contribute to cancer. Meanwhile, patients with the IDH mutation live longer with their cancer. 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."

"I can say this is potentially one of the most important discoveries in genetic studies on malignant gliomas, in the low-grade to high-grade forms of the tumor," Dr. Yan said. "The results are so clear cut. I have been doing intensive genetic studies in brain cancers for six years, and I have never seen gene mutations as striking as in this study."

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