Difference between revisions of "CNS5:Diffuse hemispheric glioma, H3 G34-mutant"
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==Genetic Diagnostic Testing Methods== | ==Genetic Diagnostic Testing Methods== | ||
| − | <br /> | + | * Targeted sequencing to identify c.103G>A p.G35R (G34R), c.103G>C p.G35R (G34R), or c.104G>T p.G35V (G34V) is diagnostic for G34-DHG. |
| + | * Pan-cancer sequencing will likely detect concurrent mutations in TP53, ATRX, PDGFRA etc. | ||
| + | * DNA methylation and gene expression profiling can be used to differentiate G34-DHG with other glioma subgroups. | ||
| + | * MGMT promoter methylation can be assessed by methylation specific polymerase chain reaction analysis (Bisulfite treated DNA undergoes real-time PCR)<br /> | ||
==Familial Forms== | ==Familial Forms== | ||
Revision as of 11:54, 16 January 2023
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
| Finding | Marker |
|---|---|
| Positive (universal) | MAP2, FOXG1, Ki-67, H3.3 p.G35R or p. G35V |
| Positive (subset) | GFAP (GBM), synaptophysin (embryonal tumor), p53 |
| Negative (universal) | ATRX, Olig2 |
| Negative (subset) |
Chromosomal Rearrangements (Gene Fusions)
Not applicable
| 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 |
|---|---|---|---|---|---|---|---|
| N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
Individual Region Genomic Gain/Loss/LOH
Overall, copy number variants (amplifications of PDGFRA and EGFR, deletion of CDKN2A, chromosome 7 gain, and chromosome 10 loss) are not common in G34-DHG [9].
| 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 |
|---|---|---|---|---|---|---|---|
| N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
Characteristic Chromosomal Patterns
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| N/A | N/A | N/A | N/A | N/A |
Gene Mutations (SNV/INDEL/Methylation)
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 |
|---|---|---|---|---|---|---|---|---|
| H3F3A p.G35R/V | chromosome modification | p.G35R 94%
p.G35V 6% |
TP53 mutations 90%;
ATRX mutations 95% MGMT promoter methylation 70% [4] |
IDH1
IDH2 H3 p.K28M/I [9] TERT |
Yes | |||
| MGMT | promoter methylation | 70% of G34-DHG | Yes (longer overall survival) |
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
- H3.3 G34R/V/D mutations impair di- or tri- methylation of lysine 36 by blocking the access to its lysine methyltransferase SETD2 and lysine demethylase KDM2A [12][13]. This attenuated interaction alters genome wide methylation level and promote tumorigenesis.
- G34-DHG demonstrates global hypomethylation pattern but MGMT promoter is frequently methylated [14][15][16]
Genes and Main Pathways Involved
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| H3F3A; p.G35/R/V | Histone modification, chromatin remodeling | Altered methylation and gene expression |
| MGMT; promoter methylatioin | DNA repair | Sensitize tumor cells to chemo- or radiotherapy. |
| TP53; mutation | Genome guardian, apoptosis | Apoptosis resistence |
| ATRX; mutation | Chromatin remodeling, alternative telomeres lengthening repression | Facilitae alternative lengthening of telomeres |
Genetic Diagnostic Testing Methods
- Targeted sequencing to identify c.103G>A p.G35R (G34R), c.103G>C p.G35R (G34R), or c.104G>T p.G35V (G34V) is diagnostic for G34-DHG.
- Pan-cancer sequencing will likely detect concurrent mutations in TP53, ATRX, PDGFRA etc.
- DNA methylation and gene expression profiling can be used to differentiate G34-DHG with other glioma subgroups.
- MGMT promoter methylation can be assessed by methylation specific polymerase chain reaction analysis (Bisulfite treated DNA undergoes real-time PCR)
Familial Forms
Put your text here
Additional Information
Put your text here
Links
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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) - ↑ 4.0 4.1 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) - ↑ 9.0 9.1 Sturm, Dominik; et al. (2012-10-16). "Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma". Cancer Cell. 22 (4): 425–437. doi:10.1016/j.ccr.2012.08.024. ISSN 1878-3686. PMID 23079654.
- ↑ Chen, Carol C. L.; et al. (2020-12-10). "Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis". Cell. 183 (6): 1617–1633.e22. doi:10.1016/j.cell.2020.11.012. ISSN 1097-4172. PMC 7791404 Check
|pmc=value (help). PMID 33259802 Check|pmid=value (help). - ↑ Lucas, Calixto-Hope G.; et al. (2021-11-02). "Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy". Neuro-Oncology. 23 (11): 1974–1976. doi:10.1093/neuonc/noab184. ISSN 1523-5866. PMC 8628364 Check
|pmc=value (help). PMID 34519829 Check|pmid=value (help). - ↑ Shi, Leilei; et al. (2018-05-25). "Histone H3.3 G34 Mutations Alter Histone H3K36 and H3K27 Methylation In Cis". Journal of Molecular Biology. 430 (11): 1562–1565. doi:10.1016/j.jmb.2018.04.014. ISSN 1089-8638. PMC 6450091. PMID 29689253.
- ↑ Cheng, Zhongjun; et al. (2014-08-15). "A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36". Genes & Development. 28 (16): 1758–1771. doi:10.1101/gad.246561.114. ISSN 1549-5477. PMC 4197961. PMID 25128496.
- ↑ Sturm, Dominik; et al. (2012-10-16). "Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma". Cancer Cell. 22 (4): 425–437. doi:10.1016/j.ccr.2012.08.024. ISSN 1878-3686. PMID 23079654.
- ↑ 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.
- ↑ Wan, Yi Ching Esther; et al. (2018). "Histone H3 Mutations in Cancer". Current Pharmacology Reports. 4 (4): 292–300. doi:10.1007/s40495-018-0141-6. ISSN 2198-641X. PMC 6061380. PMID 30101054.
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