Our findings implicate mutations in the NADP+-dependent isocitrate dehydrogenase genes, IDH1 and IDH2, in the pathogenesis of malignant gliomas. Gliomas with IDH mutations were clinically and genetically distinct from gliomas with wild-type IDH genes. Notably, two subtypes of gliomas of WHO grade II or III (astrocytomas and oligodendrogliomas) often carried IDH mutations but not other genetic alterations that are detectable relatively early during the progression of gliomas. 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. The identification of IDH1 mutations in 10 of 10 oligoastrocytomas and anaplastic oligoastrocytomas, tumors with morphologic features of both cell types, supports this conjecture.
Mutations in IDH1
were not identified in any pilocytic astrocytomas of WHO grade I, indicating that these tumors arise through a different mechanism. This conclusion is consistent with clinical observations that pilocytic astrocytomas rarely if ever undergo malignant transformation2
and with recent data indicating that a duplication at 7q34 producing a BRAF
fusion gene occurs frequently in pilocytic astrocytomas but not higher-grade gliomas.22
In each of the tested mutations, the enzymatic activity of the IDH proteins was eliminated. A previous study showed that in vitro substitution of glutamate for arginine at residue 132 of IDH1 (an alteration not observed in patients) resulted in a catalytically inactive enzyme.23
Although our results demonstrate an effect of the mutations on the function of the IDH1 protein, they do not necessarily mean that the mutations are inactivating. For example, the mutant proteins that preclude the use of isocitrate as substrate could allow other, asyet-unknown substrates to be used by the enzyme, thereby conferring a gain rather than a loss of activity. If future studies confirm this possibility, mutant IDH could become a target for therapeutic intervention.
Our results have important practical implications. Historically, glioblastomas have been divided into cancers that arise from low-grade gliomas (secondary tumors) and those without such an antecedent (primary tumors).5,6
Secondary tumors account for only 5% of all glioblastomas. The finding that IDH1
is mutated in the vast majority of WHO grade II or III gliomas and in the secondary glioblastomas that develop from these precursors provides a biologic explanation for this clinical categorization: tumors with mutated NADP+
-dependent isocitrate dehydrogenases comprise a specific subgroup of glioblastomas.
The localization of IDH1
mutations to a single amino acid (R132 and R172, respectively) simplifies the use of this genetic alteration for diagnostic purposes. For example, IDH
mutation tests could help distinguish pilocytic astrocytomas (WHO grade I) from diffuse astrocytomas (WHO grade II), since these lesions can sometimes be difficult to categorize solely on the basis of histopathological criteria.2