CNS5:Diffuse hemispheric glioma, H3 G34-mutant
Primary Author(s)*
Xiaolin Hu, PhD, Sema4 OpCo Inc.
Cancer Category/Type
Gliomas, glioneuronal tumors, and neuronal tumors / Pediatric-type diffuse high-grade gliomas
Cancer Sub-Classification / Subtype
Diffuse hemispheric glioma, H3 G34–mutant
Definition / Description of Disease
Diffuse hemispheric glioma, H3 G34–mutant (G34-DHG) is a newly recognized tumor entity that is characterized by point mutations in the H3-3A (H3F3A) gene, encoding for histone variant H3.3 [1][2]. Point mutations tend to be clustered at codon 34 including c.103G>A p.G35R (G34R), c.103G>C p.G35R (G34R), or rarely c.104G>T p.G35V (G34V) [1]. The distinct tumor entity is featured with aggressive glioma that arises from cerebral hemispheres and DHG is included in WHO 5th edition as CNS grade 4 tumor type.
Synonyms / Terminology
Pediatric glioblastoma, H3.3 G34–mutant (not recommended)
Epidemiology / Prevalence
G34-DHG is reported to account for approximately 15% of high grade gliomas (HGSs) and typically affect adolescents and young adults with a median age at diagnosis of 15.8 years old [3][4]. Studies have shown that there is a gender difference with male to female ratio of 1.4:1 [5][6].
Clinical Features
Site dependent neurological symptoms including epileptic seizure, focal deficit, increased intracranial hypertension (headache, nausea and vomiting) [7].
| Signs and Symptoms | epileptic seizure, focal deficit, increased intracranial hypertension |
| Laboratory Findings | MRI in T2 hyperintense shows bulky cortical mass most commonly seen in the parietal or temporal lobe. Multifocal lesions and/or leptomeningeal dissemination can be seen along with necrosis, cysts, hemorrhage and calcification [8]. |
Sites of Involvement
- Usually involves cerebral hemispheres
- Occasionally across the midline and disseminate to leptomeningeal structures.
Morphologic Features
- Grossly, grey/tan solid mass within cortical and subcortical region with soft consistence, necrotic and hemorrhagic features.
- Microscopically, heterogenous histological appearance including glioblastoma (GBM) and central nervous system embryonal tumor. GBM typically presents with highly cellularity, infiltrative astrocytic tumor. High mitotic activity and microvascular proliferation and necrosis are frequently seen. Embryonal tumors show hyperchromatic nuclei and scant cytoplasm with occasionally Homer-Wright rosettes appearance.
Immunophenotype
Put your text here and fill in the table
| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE CD1 |
| Positive (subset) | EXAMPLE CD2 |
| Negative (universal) | EXAMPLE CD3 |
| Negative (subset) | EXAMPLE CD4 |
Chromosomal Rearrangements (Gene Fusions)
Put your text here and fill in the table
| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE t(9;22)(q34;q11.2) | EXAMPLE 3'ABL1 / 5'BCR | EXAMPLE der(22) | EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference) |
Yes | No | Yes | EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table
| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE
7 |
EXAMPLE Loss | EXAMPLE
chr7:1- 159,335,973 [hg38] |
EXAMPLE
chr7 |
Yes | Yes | No | EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE
8 |
EXAMPLE Gain | EXAMPLE
chr8:1-145,138,636 [hg38] |
EXAMPLE
chr8 |
No | No | No | EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference). |
Characteristic Chromosomal Patterns
Put your text here
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
Gene Mutations (SNV/INDEL)
Put your text here and fill in the table
| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
Put your text here
Genes and Main Pathways Involved
Put your text here and fill in the table
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
Put your text here
Familial Forms
Put your text here
Additional Information
Put your text here
Links
Put your text placeholder here (use "Link" icon at top of page)
References
- ↑ 1.0 1.1 Schwartzentruber, Jeremy; et al. (2012-01-29). "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma". Nature. 482 (7384): 226–231. doi:10.1038/nature10833. ISSN 1476-4687. PMID 22286061.
- ↑ Wu, Gang; et al. (2012-01-29). "Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas". Nature Genetics. 44 (3): 251–253. doi:10.1038/ng.1102. ISSN 1546-1718. PMC 3288377. PMID 22286216.
- ↑ Picart, Thiébaud; et al. (2021-01). "Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults". Neuro-Oncology Advances. 3 (1): vdab061. doi:10.1093/noajnl/vdab061. ISSN 2632-2498. PMC 8156974 Check
|pmc=value (help). PMID 34056608 Check|pmid=value (help). Check date values in:|date=(help) - ↑ Crowell, Cameron; et al. (2022-01). "Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors". Neuro-Oncology Advances. 4 (1): vdac133. doi:10.1093/noajnl/vdac133. ISSN 2632-2498. PMC 9466272 Check
|pmc=value (help). PMID 36105387 Check|pmid=value (help). Check date values in:|date=(help) - ↑ Korshunov, Andrey; et al. (2016-01). "Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity". Acta Neuropathologica. 131 (1): 137–146. doi:10.1007/s00401-015-1493-1. ISSN 1432-0533. PMID 26482474. Check date values in:
|date=(help) - ↑ Mackay, Alan; et al. (2017-10-09). "Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma". Cancer Cell. 32 (4): 520–537.e5. doi:10.1016/j.ccell.2017.08.017. ISSN 1878-3686. PMC 5637314. PMID 28966033.
- ↑ Picart, Thiébaud; et al. (2021). "Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults". Neuro-Oncology Advances. 3 (1): vdab061. doi:10.1093/noajnl/vdab061. ISSN 2632-2498. PMC 8156974 Check
|pmc=value (help). PMID 34056608 Check|pmid=value (help). - ↑ Vettermann, Franziska J.; et al. (2018-12). "Characterization of Diffuse Gliomas With Histone H3-G34 Mutation by MRI and Dynamic 18F-FET PET". Clinical Nuclear Medicine. 43 (12): 895–898. doi:10.1097/RLU.0000000000002300. ISSN 1536-0229. PMID 30358620. Check date values in:
|date=(help)
(use "Cite" icon at top of page)
EXAMPLE Book
- Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.