Diffuse astrocytoma

Summary

Diffuse astrocytoma (MONDO:0016686) is a disease with 2 cohort genes and 6 clinical trials. Molecularly, FGFR3::TACC3 Fusion confers sensitivity to Fexagratinib in Diffuse Astrocytoma (CIViC Level C); 1 further subtype–drug associations are mapped below. Top therapeutic interventions include dabrafenib, trametinib, and eflornithine.

At a glance

• Prevalence: 1-9 / 1 000 000 (United States) [Orphanet-validated]
• Cohort genes: 2
• Clinical trials: 6
• Precision-medicine evidence (CIViC): 2 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.48	United States	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	diffuse astrocytoma
Mondo ID	MONDO:0016686
Orphanet	251595
DOID	DOID:4857
NCIT	C7173
UMLS	C0280785
MedGen	83708
GARD	0005907
Is cancer (heuristic)	no

Also known as: astrocytoma, diffuse · astrocytoma, diffuse, malignant · diffuse astrocytoma · fibrillary astrocytoma (histologic variant) · gemistocytic astrocytoma (histologic variant) · grade II astrocytic neoplasm · grade II astrocytic tumor · grade II astrocytic tumour · grade II astrocytoma · low-grade diffuse astrocytoma · protoplasmic astrocytoma (histologic variant) · WHO grade II astrocytoma

Data availability: 11 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › nervous system neoplasm › neuroepithelial neoplasm › glioma › astrocytic tumor › astrocytoma (excluding glioblastoma) › low-grade astrocytoma › diffuse astrocytoma

Related subtypes (4): pituicytoma, pleomorphic xanthoastrocytoma, pilocytic astrocytoma, subependymal giant cell astrocytoma

Subtypes (4): protoplasmic astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, diffuse astrocytoma, MYB- or MYBL1-altered

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
H3-3A	HGNC:4764	ENSG00000163041	P84243	Histone H3.3	civic_evidence
H3C2	HGNC:4776	ENSG00000286522	P68431	Histone H3.1	civic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
H3-3A	Histone H3.3	Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes.
H3C2	Histone H3.1	Core component of nucleosome.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
H3-3A	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, Histone-fold
H3C2	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, Histone-fold

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	1
monocyte	1
ventricular zone	1
adrenal tissue	1
bone marrow cell	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
H3-3A	134	ubiquitous	marker	ganglionic eminence, monocyte, ventricular zone
H3C2	94	ubiquitous	marker	adrenal tissue, colonic epithelium, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
H3C2	3,550
H3-3A	1,595

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H3C2	P68431	548
H3-3A	P84243	103

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RNA Polymerase I Promoter Opening	2	184.2×	1e-04	H3-3A, H3C2
DNA methylation	2	178.4×	1e-04	H3-3A, H3C2
FXIIa activates plasma kallikrein-kinin system	2	173.0×	1e-04	H3-3A, H3C2
SIRT1 negatively regulates rRNA expression	2	170.4×	1e-04	H3-3A, H3C2
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3	2	167.9×	1e-04	H3-3A, H3C2
Assembly of the ORC complex at the origin of replication	2	165.5×	1e-04	H3-3A, H3C2
Chromatin modifications during the maternal to zygotic transition (MZT)	2	163.1×	1e-04	H3-3A, H3C2
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	2	163.1×	1e-04	H3-3A, H3C2
Condensation of Prophase Chromosomes	2	156.4×	1e-04	H3-3A, H3C2
Defective pyroptosis	2	156.4×	1e-04	H3-3A, H3C2
PRC2 methylates histones and DNA	2	152.3×	1e-04	H3-3A, H3C2
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	2	152.3×	1e-04	H3-3A, H3C2
CHD6, CHD7, CHD8, CHD9 subfamily	2	148.3×	1e-04	H3-3A, H3C2
Transcriptional regulation by small RNAs	2	144.6×	1e-04	H3-3A, H3C2
NuRD complex assembly	2	141.0×	1e-04	H3-3A, H3C2
Meiotic recombination	2	129.8×	1e-04	H3-3A, H3C2
Interaction of NuRD complexes with transcription factors	2	126.9×	1e-04	H3-3A, H3C2
Transcriptional regulation of granulopoiesis	2	125.5×	1e-04	H3-3A, H3C2
Pre-NOTCH Transcription and Translation	2	122.8×	1e-04	H3-3A, H3C2
B-WICH complex positively regulates rRNA expression	2	121.5×	1e-04	H3-3A, H3C2
RNA Polymerase I Promoter Escape	2	121.5×	1e-04	H3-3A, H3C2
Formation of the beta-catenin:TCF transactivating complex	2	120.2×	1e-04	H3-3A, H3C2
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	2	120.2×	1e-04	H3-3A, H3C2
Negative Regulation of CDH1 Gene Transcription	2	120.2×	1e-04	H3-3A, H3C2
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	117.7×	1e-04	H3-3A, H3C2
Regulation of PD-L1(CD274) transcription	2	108.8×	2e-04	H3-3A, H3C2
CHD1 and CHD2 subfamily	2	108.8×	2e-04	H3-3A, H3C2
Regulation of endogenous retroelements by KRAB-ZFP proteins	2	106.7×	2e-04	H3-3A, H3C2
NoRC negatively regulates rRNA expression	2	104.8×	2e-04	H3-3A, H3C2
Amyloid fiber formation	2	102.9×	2e-04	H3-3A, H3C2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomere organization	2	624.1×	4e-05	H3-3A, H3C2
nucleosome assembly	2	140.4×	5e-04	H3-3A, H3C2
negative regulation of chromosome condensation	1	2106.5×	0.003	H3-3A
pericentric heterochromatin formation	1	1685.2×	0.003	H3-3A
subtelomeric heterochromatin formation	1	766.0×	0.005	H3-3A
muscle cell differentiation	1	421.3×	0.007	H3-3A
oocyte maturation	1	300.9×	0.008	H3-3A
nucleus organization	1	280.9×	0.008	H3-3A
epigenetic regulation of gene expression	1	191.5×	0.010	H3C2
embryo implantation	1	175.5×	0.010	H3-3A
single fertilization	1	91.6×	0.016	H3-3A
positive regulation of cell growth	1	91.6×	0.016	H3-3A
male gonad development	1	78.0×	0.017	H3-3A
spermatid development	1	72.6×	0.017	H3-3A
multicellular organism growth	1	68.5×	0.017	H3-3A
osteoblast differentiation	1	60.6×	0.018	H3-3A
cell population proliferation	1	51.4×	0.020	H3-3A
chromatin organization	1	49.6×	0.020	H3C2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
H3-3A	0	0
H3C2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
H3-3A	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	H3-3A, H3C2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
H3-3A	6	—
H3C2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
PHASE4	1
PHASE1/PHASE2	1
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT03180502	PHASE2	ACTIVE_NOT_RECRUITING	Proton Beam or Intensity-Modulated Radiation Therapy in Preserving Brain Function in Patients With IDH Mutant Grade II or III Glioma
NCT07468136	PHASE1/PHASE2	NOT_YET_RECRUITING	Retifanlimab With or Without Difluoromethylornithine for the Treatment of Progressive High Grade Gliomas
NCT02684058	PHASE2	COMPLETED	Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Pediatric Patients With BRAF V600 Mutation Positive LGG or Relapsed or Refractory HGG Tumors
NCT04541082	PHASE1	RECRUITING	Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms
NCT04065776	Not specified	RECRUITING	Evaluation of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DABRAFENIB	4	2
TRAMETINIB	4	2
EFLORNITHINE	4	1
RETIFANLIMAB	4	1
EFLORNITHINE, (S)-	2	1
ONC-206	1	1
CHEMBL5433950	0	2
CHEMBL4446459	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 2 predictive associations from 2 curated evidence items; also 4 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
FGFR3::TACC3 Fusion	Fexagratinib	Sensitivity/Response	CIViC C	EID9242
NF1 D1644H AND NF1 Q1189*	Selumetinib	Sensitivity/Response	CIViC C	EID12342