The Role of IDH Mutation in Human Brain Tumors

Recent studies have identified mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) in gliomas, human brain tumors that are currently incurable. Sheri Holmen, PhD, was the first to show that IDH mutations, on the appropriate genetic background, resulted in glioma initiation and growth. This discovery provided the basis of a pre-clinical model for testing the contribution of other molecular alterations to the pathogenesis of, and the effects of various treatments on, these tumors. Howard Colman, MD, PhD, and colleagues subsequently demonstrated that increased DNA alterations were associated with higher-grade gliomas and worse prognoses. Using the Utah Population Database, they confirmed that a particular DNA germline variant was associated with elevated risk of developing oligodendrogliomas, a subtype of IDH-mutant tumors. They also found that this allele was associated with increased risk of other cancers. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) considered elements of this work when drafting recommended revisions to the World Health Organization's guidelines around diagnosing and grading IDH-mutant gliomas.