The Role of IDH Mutation in Human Brain Tumors

Graphic- The Role of IDH Mutation in Human Brain Tumors
A novel preclinical model (IDH1R132H PDGFA- Cre) demonstrates that IDH mutations cooperate with other genetic alterations to promote brain tumor formation and growth. This model can be used to test the effects of various treatments on these tumors. For example, poly(ADP-ribose polymerase (PARP) inhibition and chemotherapy reduced tumor cell viability in these models.

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. 


Issues Icon

DNA copy number analysis of grade ii-iii and grade iv gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status. Cohen A, Sato M, Aldape K, Mason CC, Alfaro-Munoz K, Heathcock L, South ST, Abegglen LM, Schiffman JD, Colman H.  Acta Neuropathologica Communications. 2015 June 20;3:34.

Issues Icon

Mutant idh1 promotes glioma formation in vivo. Philip, Beatrice, Yu DX, Silvis MR, Shin CH, Robinson JP, Robinson GL, Welker AE, et al.  Cell Reports. 2018 May 1;23(5):1553.

Issues Icon

cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C, Holland EC, et al. Acta Neuropathologica. 2020 March;139(3):603.