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Published on: January 14, 2014
Beyond the Tumor Mass: From Initiating Clones to Overt Isocitrate Dehydrogenase-Mutant Gliomas
Jung Won Park1, Jeong Ho Lee1,2, Seok-Gu Kang3,4,5
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Abstract:
Isocitrate dehydrogenase (IDH)-mutant gliomas are primary malignant brain tumors defined by recurrent mutations in IDH1/2 genes and characterized by distinct molecular subtypes and relatively favorable clinical outcomes. Although these mutations represent early and defining events, recent data suggest that IDH1 mutant glial progenitor cells can reside within the histologically normal-appearing peritumoral cortex, indicating that cells harboring the founding driver mutation can persist beyond the tumor mass while retaining nonmalignant features. These observations challenge a purely gene-centric view of gliomagenesis. In this essay, we review emerging data supporting a multistep and context-dependent model in which the mutant IDH enzyme establishes an epigenetically altered cellular state, with subsequent genetic alterations and lineage-specific constraints that shape malignant progression. We further discuss the conceptual distinction between the "cell-of-mutation" and the "cell-of-origin" and consider how temporal stratification of tumor evolution may inform stage-specific therapeutic strategies along the transition from initiating clones beyond the tumor mass to overt tumors.
Insights
Isocitrate dehydrogenase (IDH)-mutant gliomas originate from cells with IDH mutations that can exist outside the tumor. This suggests a multistep process for brain tumor development, not just gene mutation.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Genetics
Background:
- Isocitrate dehydrogenase (IDH)-mutant gliomas are primary malignant brain tumors characterized by IDH1/2 gene mutations.
- These mutations are early events, but IDH1 mutant cells can exist in peritumoral cortex, challenging a gene-centric view of gliomagenesis.
Purpose of the Study:
- To review emerging data supporting a multistep, context-dependent model of gliomagenesis.
- To discuss the distinction between the "cell-of-mutation" and "cell-of-origin."
- To explore how temporal stratification of tumor evolution can inform therapeutic strategies.
Main Methods:
- Literature review of emerging data on IDH-mutant gliomas.
- Conceptual analysis of gliomagenesis models.
- Discussion of therapeutic implications.
Main Results:
- Emerging data support a multistep model where mutant IDH establishes an epigenetically altered state, followed by genetic alterations and lineage constraints.
- Cells harboring the founding mutation can persist beyond the tumor mass with nonmalignant features.
- A conceptual distinction between "cell-of-mutation" and "cell-of-origin" is proposed.
Conclusions:
- Glioma development is a multistep process influenced by epigenetic changes, genetic alterations, and cellular context.
- Understanding the temporal evolution of tumor clones, including those outside the overt tumor mass, is crucial.
- Stage-specific therapeutic strategies may be informed by the transition from initiating clones to overt tumors.
