Molecular pathogenesis of diffuse gliomas
- Tracy Batchelor, MD, MPH
Tracy Batchelor, MD, MPH
- Giovanni Armenise Professor of Neurology
- Harvard Medical School
- David N Louis, MD
David N Louis, MD
- Massachusetts General Hospital
- Benjamin Castleman Professor of Pathology
- Harvard Medical School
- Section Editors
- Jay S Loeffler, MD
Jay S Loeffler, MD
- Section Editor — Neurooncology
- Professor of Radiation Oncology
- Harvard Medical School
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
Gliomas are primary brain tumors that display histological features of glial cells (ie, astrocytes, oligodendrocytes, and ependymal cells). The diffuse gliomas are the most common types and generally affect the cerebral hemispheres of adults. They are classified based upon their line of differentiation and are graded according to their histological degree of malignancy.
Diffuse gliomas are classified according to the 2016 World Health Organization (WHO) system by both histologic and molecular characteristics as isocitrate dehydrogenase (IDH)-mutant astrocytomas, IDH-wildtype astrocytomas, and IDH-mutant and 1p19q-codeleted oligodendrogliomas . (See "Classification and pathologic diagnosis of gliomas".)
The pathogenesis and biology of diffuse gliomas are reviewed here. The pathologic diagnosis, clinical manifestations, diagnosis, and treatment of these tumors are discussed separately. (See "Classification and pathologic diagnosis of gliomas" and "Clinical manifestations and initial surgical approach to patients with high-grade gliomas" and "Adjuvant radiation therapy for high-grade gliomas" and "Initial postoperative therapy for glioblastoma and anaplastic astrocytoma".)
CELL OF ORIGIN
Current studies suggest that high-grade gliomas arise from neural progenitor cells, but the precise stage of differentiation of such target cells (ie, stem cells versus progenitor cells) is not clear. High-grade gliomas contain multipotent tumor stem cells that are responsible for populating and repopulating the tumors [2,3]. These tumor stem cells may be transformed variants of normal neural progenitor cells. The existence of these tumor stem cells may have therapeutic implications, since therapies that do not ablate the tumor stem cells will be ineffective in eradicating the tumor. Nonetheless, the cell of origin of high-grade gliomas remains uncertain, and the possibility that these tumors arise from a fully differentiated cell type, such as a mature glial cell, has not been excluded.
ADULT DIFFUSE GLIOMAS
Understanding of the molecular genetic basis of high-grade gliomas has increased markedly over the last two decades [4-7]. This knowledge has provided insight into the biological basis of high-grade glioma formation and progression. Importantly, this information has permitted the generation of novel genetically engineered murine models of diffuse high-grade glioma [8,9]. Some of these molecular changes may represent potential targets for future gene or molecular pharmacological therapies. However, single agent therapeutic approaches may be confounded by the sometimes remarkable heterogeneity within individual high-grade gliomas, which has been demonstrated at the regional and cellular levels [10,11].
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- CELL OF ORIGIN
- ADULT DIFFUSE GLIOMAS
- Formation of astrocytoma
- - TP53 gene
- - Isocitrate dehydrogenase (IDH) gene
- - ATRX gene
- Formation of oligodendroglial tumors
- Transition to high-grade glioma
- - Checkpoint alterations
- - PTEN inactivation
- - Growth factor amplification and overexpression
- - Angiogenesis
- - Treatment effects and hypermutation phenotype
- Genetic subsets of glioblastoma
- - Primary versus secondary glioblastoma
- - Hypermethylation phenotype
- - Gene expression profile subtypes
- PEDIATRIC DIFFUSE GLIOMAS
- Lower grade astroctyoma
- High-grade glioma