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Santiago Haase et al.
of the University of Michigan School of Medicine reviewed the gene mutations, epigenetic modifications and treatment strategies of high-grade gliomas in children, published in the December 2020 issue of the International
Journal of Molecular Sciences.
- Excerpted from the article chapter
【Ref: Haase S, et al.
Int J Mol Sci.
2020 Dec 17; 21(24):9654.
doi: 10.
3390/ijms21249654.
】
Research background
Pediatric high-grade glioma (pHGG) accounts for 8-12% of childhood brain tumors, with a mean median survival of 9-15 months and a 5-year survival rate of less than 20%.
Among them, the incidence of pHGG located in the cerebral hemisphere is about 0.
12 per 100,000, which is the leading cause
of cancer-related death in children and adolescents.
At present, the pathogenesis of pHGG is not completely clear, and there is no effective treatment
.
High-throughput sequencing provides new opportunities
for pHGG research at the molecular level.
Santiago Haase et al.
of the University of Michigan School of Medicine reviewed the gene mutations, epigenetic modifications and treatment strategies of high-grade gliomas in children, published in the December 2020 issue of the International
Journal of Molecular Sciences.
Study results
The main contents of the review are as follows:
1.
Histone variants are associated with
the occurrence of pHGG in cerebral hemispheres.
The human histone subunits H2A, H2B, H3 and H4 each provide two molecules to form an octamer, form a nucleosome with DNA, and participate in DNA replication, repair and recombination
.
Among them, the H3.
3 variant is encoded by the H3F3A and H3F3B genes, and the HIRA, DAXX and ATRX complexes related to H3.
3 regulate chromatin activation, telomere and surrounding area activity
.
Post-transcriptional modification of H3 is closely
related to epigenetic mutations and pHGG.
2.
About 20% of cerebral hemisphere pHGG can detect H3F3A gene mutations, and the glycine mutation at position 34 is arginine or valine, that is, H3.
3 G34R/V mutation
.
Patients with pHGG with G34R/V mutations have a poor prognosis, with a mean median survival of 18 months and a 2-year survival rate of 27.
3%.
Tumor cells carrying this mutation exhibit loss of ATRX function and partial DAXX telomere instability, as well as an overall decrease
in DNA methylation levels.
H3.
3 G34R/V is the only histone mutation variant
of pHGG with significantly elevated methylation levels at the MGMT promoter.
3.
H3K36 trimethylation (K36me3) only decreased the G34R/V mutant histone itself, but had no effect
on the distribution of wild-type histone K36me3.
NSD1-3 and SETD2 are the main H3K36 methyltransferases, while only SETD2 catalyzes K36 trimethylation
.
H3.
3 G34 mutations not only inhibit SETD2 interactions, but also interfere with the interaction between histone tails and proteins that recognize K36 tags, such as mismatch repair protein (MMR) MutSα
.
4.
G34R/V mutation is related
to DNA damage repair response.
SETD2 insufficiency cells will experience decreased K36me3 levels, microsatellite instability, increased mutation frequency, and MMR deletion phenotype
.
Compared with the same gene H3F3A control group, pHGG cells expressing exogenous H3F3A-G34R expressed an increased mutation and showed the same trend
on pHGG patient sample data.
The promoter encoding of the MGMT gene is an enzyme involved in DNA repair; The promoter of the MGMT gene in G34R tumors is significantly increased, which may lead to decreased MGMT expression and increased sensitivity of tumor cells to
temozolomide.
5.
ATRX participates in the formation of DAXX/ATRX complexes, which deposition H3.
3 into transcriptionally active loci
.
Studies have shown that ATRX maintains chromosomal stability and DNA repair processes
.
ATRX inactivation causes selective prolongation of telomeres in pHGG cells, which in turn leads to infinite division of cancer cells
.
In addition, loss of ATRX can lead to increased cell migration and epigenetic changes
.
6.
TP53 and PDGFR mutations
.
The TP53 pathway is the most common pathway for expression disorders in pHGG
.
P53 is associated
with precise DNA replication, damage repair, apoptosis, and extramitochondrial membrane permeability.
About 38% of children's hemisphere pHGG has a TP53 mutation
.
PDGFR is also a common mutated gene, with 10% PDGFR mutations and 7% amplification in children's hemisphere pHGG
.
PDGFRA mutations were significantly associated
with TP53 (>70%), ATRX (>60%), and H3F3A G34R/V (>40%) mutations.
7.
PTEN and PI3K/AKT signaling pathways
.
PTEN is involved in centrosome stability, cell circulation, and DNA homologous recombinant repair
.
Mutations are seen in approximately 9% of patients
with non-brainstem pHGG.
The loss of PTEN increases the level of Akt in pHGG cells, which in turn leads to increased
cell aggressiveness.
8.
Mutations
in other genes.
Raf kinase activating mutations are the most common form of BRAF-V600 mutation and are often associated with the PI3K/AKT signaling pathway, and their mutations occur in approximately 9% of non-brainstem pHGG patients
.
NTRK rearrangement leads to gene fusion, which occurs in approximately 10% of non-brainstem pHGGs, rising to 40%
in patients under three years of age.
IDH mutations are relatively rare in children's hemisphere pHGG, occurring in less than 4%, but patients with IDH mutations have a better
prognosis than wild-type IDH.
Other relatively rare mutations include NF1 and H3F3A K27M mutations, the latter occurring mainly in the brainstem pHGG, with a non-brainstem pHGG incidence of only about
1.
3%.
9.
In childhood hemisphere pHGG, there are four genes, including PDGFR, CDK4, EGFR, and NF1, that determine the proportion of
transcriptional differentiation of glioma cells.
Among them, PDGFRA amplified/mutant tumors were dominated by oligodendrocytes precursor (OPC)-like cells, CDK4 amplified tumors were dominated by neural precursor cells (NPCs), EGFR amplified tumors were dominated by astrocytes, and NF1 was mainly mesenchymal cells
.
Conclusion of the study
Finally, the authors note that the review explains the pathogenesis of high-grade gliomas in children from the perspective of genetic mutation and epigenetics; Taking specific mutations as the entry point for pHGG research can help improve clinical treatment decisions and is expected to realize individualized treatment
of pHGG patients.
