Pediatric high-grade glioma

Summary

Pediatric high-grade glioma (MONDO:1010030) is a cancer with 5 cohort genes (4 CIViC-evidence somatic drivers; 6 ClinVar predisposition records) and 2 clinical trials. Top therapeutic interventions include hiltonol.

At a glance

• Classification: Cancer
• Cohort genes: 5
• ClinVar variants: 6
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pediatric high-grade glioma
Mondo ID	MONDO:1010030
NCIT	C202298
UMLS	C5908419
MedGen	1861427
GARD	0027222
Is cancer (heuristic)	yes

Also known as: childhood malignant glioma · pHGG

Data availability: 6 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › childhood malignant neoplasm › pediatric high-grade glioma

Related subtypes (29): childhood oligodendroglioma, pediatric osteosarcoma, pediatric fibrosarcoma, childhood choroid plexus carcinoma, childhood central nervous system primitive neuroectodermal neoplasm, childhood brain stem neoplasm, pediatric angiosarcoma, pediatric mesenchymal chondrosarcoma, pediatric liposarcoma, pediatric lymphoma, childhood malignant mesenchymoma, pediatric myxoid chondrosarcoma, childhood botryoid rhabdomyosarcoma, pediatric intraocular retinoblastoma, childhood cerebral astrocytoma, childhood epithelioid sarcoma, childhood pleomorphic rhabdomyosarcoma, pediatric infratentorial ependymoma, pediatric supratentorial ependymoma, childhood malignant schwannoma, pediatric extraocular retinoblastoma, childhood leukemia, childhood precursor T-lymphoblastic lymphoma/leukemia, malignant childhood germ cell neoplasm, pleuropulmonary blastoma, pediatric hepatocellular carcinoma, childhood malignant kidney neoplasm, childhood malignant melanoma, extrarenal rhabdoid tumor

Subtypes (1): diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 2 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3340398	NM_006767.4(LZTR1):c.320+2T>C	LZTR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
242114	NM_177438.3(DICER1):c.4616C>T (p.Thr1539Met)	DICER1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6946	NM_002485.5(NBN):c.511A>G (p.Ile171Val)	NBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374972	NM_006231.4(POLE):c.4169G>A (p.Arg1390His)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2573127	NM_000135.4(FANCA):c.3659C>T (p.Pro1220Leu)	FANCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
240569	NM_006231.4(POLE):c.5633G>A (p.Arg1878His)	POLE	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
DICER1	LoF	COADREAD,CSCC,MEL,UCEC	CIViC #9533
FANCA	Act	PRAD	CIViC #1810
LZTR1	LoF	GBM,HCC,PRAD,UCEC	CIViC #6523
POLE	Act	ACC,BLCA	CIViC #4386

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DICER1	Orphanet:276399	Familial multinodular goiter
DICER1	Orphanet:284343	DICER1 tumor-predisposition syndrome
DICER1	Orphanet:404476	Global developmental delay-lung cysts-overgrowth-Wilms tumor syndrome
DICER1	Orphanet:99757	Embryonal rhabdomyosarcoma
DICER1	Orphanet:99914	Gynandroblastoma
DICER1	Orphanet:99915	Malignant granulosa cell tumor of the ovary
DICER1	Orphanet:99916	Malignant Sertoli-Leydig cell tumor of the ovary
FANCA	Orphanet:84	Fanconi anemia
LZTR1	Orphanet:251576	Gliosarcoma
LZTR1	Orphanet:251579	Giant cell glioblastoma
LZTR1	Orphanet:2678	Familial isolated café-au-lait macules
LZTR1	Orphanet:648	Noonan syndrome
LZTR1	Orphanet:93921	Full schwannomatosis
NBN	Orphanet:1331	Familial prostate cancer
NBN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
NBN	Orphanet:647	Nijmegen breakage syndrome
POLE	Orphanet:352712	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome
POLE	Orphanet:440437	Familial colorectal cancer Type X
POLE	Orphanet:447877	Polymerase proofreading-related polyposis
POLE	Orphanet:85173	IMAGe syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DICER1	HGNC:17098	ENSG00000100697	Q9UPY3	Endoribonuclease Dicer	clinvar
FANCA	HGNC:3582	ENSG00000187741	O15360	Fanconi anemia group A protein	clinvar
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	clinvar
NBN	HGNC:7652	ENSG00000104320	O60934	Nibrin	clinvar
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DICER1	Endoribonuclease Dicer	Double-stranded RNA (dsRNA) endoribonuclease playing a central role in short dsRNA-mediated post-transcriptional gene silencing.
FANCA	Fanconi anemia group A protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
NBN	Nibrin	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	2.4×	0.608
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DICER1	Enzyme (other)	yes	3.1.26.3	RNase_III_dom, Helicase_C-like, PAZ_dom
FANCA	Other/Unknown	no		FANCA, Fanconi_A_N, Fanconi_A_C
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
NBN	Other/Unknown	no		FHA_dom, BRCT_dom, SMAD_FHA_dom_sf
POLE	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cauda epididymis	2
right testis	2
caput epididymis	1
tongue squamous epithelium	1
left testis	1
ventricular zone	1
adenohypophysis	1
pituitary gland	1
sural nerve	1
endometrium epithelium	1
mammary duct	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DICER1	295	ubiquitous	marker	cauda epididymis, caput epididymis, tongue squamous epithelium
FANCA	185	ubiquitous	marker	right testis, ventricular zone, left testis
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
NBN	299	ubiquitous	marker	endometrium epithelium, mammary duct, cauda epididymis
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DICER1	8,268
POLE	3,267
FANCA	3,036
NBN	1,989
LZTR1	1,562

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DICER1	Q9UPY3	21
POLE	Q07864	18
NBN	O60934	7
FANCA	O15360	6
LZTR1	Q8N653	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 5 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HDR through Homologous Recombination (HRR)	2	95.2×	0.010	NBN, POLE
tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis	1	951.7×	0.026	DICER1
Sensing of DNA Double Strand Breaks	1	475.8×	0.026	NBN
DNA replication initiation	1	356.9×	0.026	POLE
Small interfering RNA (siRNA) biogenesis	1	285.5×	0.026	DICER1
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	237.9×	0.026	NBN
HDR through MMEJ (alt-NHEJ)	1	219.6×	0.026	NBN
Diseases of DNA Double-Strand Break Repair	1	203.9×	0.026	NBN
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	203.9×	0.026	NBN
Resolution of D-Loop Structures	1	158.6×	0.026	NBN
Regulation of MITF-M-dependent genes involved in apoptosis	1	158.6×	0.026	DICER1
Diseases of DNA repair	1	142.8×	0.026	NBN
PCNA-Dependent Long Patch Base Excision Repair	1	129.8×	0.026	POLE
DNA Double Strand Break Response	1	119.0×	0.026	NBN
MicroRNA (miRNA) biogenesis	1	114.2×	0.026	DICER1
Impaired BRCA2 binding to PALB2	1	114.2×	0.026	NBN
Gap-filling DNA repair synthesis and ligation in GG-NER	1	109.8×	0.026	POLE
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	105.7×	0.026	NBN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	105.7×	0.026	NBN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	105.7×	0.026	NBN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	98.5×	0.026	NBN
Recognition of DNA damage by PCNA-containing replication complex	1	95.2×	0.026	POLE
Homologous DNA Pairing and Strand Exchange	1	95.2×	0.026	NBN
Termination of translesion DNA synthesis	1	86.5×	0.026	POLE
Activation of the pre-replicative complex	1	81.6×	0.026	POLE
M-decay: degradation of maternal mRNAs by maternally stored factors	1	81.6×	0.026	DICER1
Homology Directed Repair	1	77.2×	0.026	NBN
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	77.2×	0.026	NBN
Impaired BRCA2 binding to RAD51	1	77.2×	0.026	NBN
Resolution of D-loop Structures through Holliday Junction Intermediates	1	75.1×	0.026	NBN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of Schwann cell differentiation	1	1685.2×	0.009	DICER1
telomere maintenance via telomere trimming	1	1685.2×	0.009	NBN
regulation of germ cell proliferation	1	1685.2×	0.009	FANCA
peripheral nervous system myelin formation	1	1123.5×	0.009	DICER1
DNA replication proofreading	1	1123.5×	0.009	POLE
global gene silencing by mRNA cleavage	1	1123.5×	0.009	DICER1
leading strand elongation	1	842.6×	0.009	POLE
telomeric 3’ overhang formation	1	842.6×	0.009	NBN
regulation of CD40 signaling pathway	1	842.6×	0.009	FANCA
tRNA decay	1	674.1×	0.010	DICER1
negative regulation of telomere capping	1	674.1×	0.010	NBN
blastocyst growth	1	561.7×	0.010	NBN
nucleotide-excision repair, DNA gap filling	1	561.7×	0.010	POLE
negative regulation of Schwann cell proliferation	1	481.5×	0.010	DICER1
protection from non-homologous end joining at telomere	1	481.5×	0.010	NBN
DNA strand resection involved in replication fork processing	1	421.3×	0.010	NBN
siRNA processing	1	374.5×	0.010	DICER1
telomere maintenance in response to DNA damage	1	374.5×	0.010	NBN
regulation of regulatory T cell differentiation	1	374.5×	0.010	FANCA
R-loop processing	1	337.0×	0.010	NBN
double-strand break repair via alternative nonhomologous end joining	1	337.0×	0.010	NBN
DNA double-strand break processing	1	306.4×	0.010	NBN
RISC complex assembly	1	306.4×	0.010	DICER1
miRNA metabolic process	1	280.9×	0.010	DICER1
homologous recombination	1	280.9×	0.010	NBN
t-circle formation	1	280.9×	0.010	NBN
apoptotic DNA fragmentation	1	240.7×	0.011	DICER1
base-excision repair, gap-filling	1	224.7×	0.011	POLE
pre-miRNA processing	1	224.7×	0.011	DICER1
regulation of DNA-templated DNA replication initiation	1	210.7×	0.011	NBN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DICER1	0	0
FANCA	0	0
LZTR1	0	0
NBN	0	0
POLE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DICER1	8	Binding:8
NBN	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DICER1	3.1.26.3	ribonuclease III
POLE	2.7.7.7	DNA-directed DNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DICER1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	FANCA, LZTR1, NBN, POLE

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DICER1	8	—
FANCA	0	—
LZTR1	0	—
NBN	2	—
POLE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06894979	PHASE1	RECRUITING	Testing the Addition of an Anti-Cancer Drug, AZD1390, During Radiation Therapy for Newly Diagnosed High Grade Glioma, Diffuse Midline Glioma, or Diffuse Intrinsic Pontine Glioma
NCT01130077	PHASE1	COMPLETED	A Pilot Study of Glioma Associated Antigen Vaccines in Conjunction with Poly-ICLC in Pediatric Gliomas

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HILTONOL	2	1