Pineoblastoma

Summary

Pineoblastoma (MONDO:0016722) is a disease with 2 cohort genes and 19 clinical trials. Top therapeutic interventions include etoposide phosphate, bevacizumab, and isotretinoin.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 13
• Phenotypes (HPO): 19
• Clinical trials: 19

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.02	Europe	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0010799	Pinealoma	Obligate (100%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0002516	Increased intracranial pressure	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000619	Impaired convergence	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0001085	Papilledema	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0003470	Paralysis	Occasional (5-29%)
HP:0007045	Midline brain calcifications	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0007987	Progressive visual field defects	Occasional (5-29%)
HP:0009919	Retinoblastoma	Occasional (5-29%)
HP:0100576	Amaurosis fugax	Occasional (5-29%)
HP:0001254	Lethargy	Very rare (<1-4%)
HP:0004372	Reduced consciousness/confusion	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pineoblastoma
Mondo ID	MONDO:0016722
EFO	EFO:1000475
Orphanet	251909
DOID	DOID:1664
NCIT	C9344
UMLS	C0205898
MedGen	104745
GARD	0009369
MedDRA	10050487
Is cancer (heuristic)	no

Also known as: pineal gland PNET · pineal gland primitive neuroectodermal neoplasm · pineal gland primitive neuroectodermal tumor · pineal gland primitive neuroectodermal tumour · pineal PNET · pineal primitive neuroectodermal neoplasm · pineal primitive neuroectodermal tumor · pineal primitive neuroectodermal tumour · pineoblastoma · pineoblastoma (WHO grade IV) · pineoblastoma, malignant · PNET of pineal gland · PNET of the pineal gland · primitive neuroectodermal neoplasm of pineal gland · primitive neuroectodermal neoplasm of the pineal gland · primitive neuroectodermal tumor of pineal gland · primitive neuroectodermal tumor of the pineal gland · primitive neuroectodermal tumour of pineal gland · primitive neuroectodermal tumour of the pineal gland

Data availability: 13 ClinVar variants · 6 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: neoplastic disease or syndrome › neoplasm › cancer › nervous system cancer › central nervous system cancer › brain cancer › supratentorial cancer › diencephalic cancer › thalamic cancer › pineal gland cancer › pineoblastoma

Related subtypes (2): malignant pineal area germ cell neoplasm, pineal gland astrocytoma

Subtypes (1): adult pineoblastoma

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

13 retrieved; paginated sample, class counts are floors:

10 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
225883	NM_177438.3(DICER1):c.4754C>G (p.Ser1585Ter)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
225884	NM_177438.3(DICER1):c.5103C>A (p.Tyr1701Ter)	DICER1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225885	NM_177438.3(DICER1):c.4633dup (p.Ser1545fs)	DICER1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225886	NM_177438.3(DICER1):c.1498A>T (p.Lys500Ter)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
225887	NM_177438.3(DICER1):c.4050+1G>A	DICER1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225888	NM_177438.3(DICER1):c.4407_4410del (p.Ser1470fs)	DICER1	Pathogenic	criteria provided, multiple submitters, no conflicts
3393485	NM_001382508.1(DROSHA):c.811C>T (p.Arg271Ter)	DROSHA	Pathogenic	no assertion criteria provided
3393486	NM_001382508.1(DROSHA):c.2883-1G>A	DROSHA	Pathogenic	no assertion criteria provided
3393487	NM_001382508.1(DROSHA):c.403_409delinsCCACTT (p.Ala135fs)	DROSHA	Pathogenic	no assertion criteria provided
3393488	NM_001382508.1(DROSHA):c.3261+1G>C	DROSHA	Pathogenic	no assertion criteria provided
3393489	NM_001382508.1(DROSHA):c.3548del (p.Asn1183fs)	DROSHA	Pathogenic	no assertion criteria provided
3393490	NM_001382508.1(DROSHA):c.2436_2439del (p.Asp814fs)	DROSHA	Pathogenic	no assertion criteria provided
3393491	NM_001382508.1(DROSHA):c.2988A>C (p.Leu996Phe)	DROSHA	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DICER1	HGNC:17098	ENSG00000100697	Q9UPY3	Endoribonuclease Dicer	clinvar
DROSHA	HGNC:17904	ENSG00000113360	Q9NRR4	Ribonuclease 3	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.
DROSHA	Ribonuclease 3	Ribonuclease III double-stranded (ds) RNA-specific endoribonuclease that is involved in the initial step of microRNA (miRNA) biogenesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	2	12.0×	0.007

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
DROSHA	Enzyme (other)	yes	3.1.26.3	RNase_III_dom, RNase_III, dsRBD_dom

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
caput epididymis	1
cauda epididymis	1
tongue squamous epithelium	1
endothelial cell	1
germinal epithelium of ovary	1
ventricular zone	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
DROSHA	283	ubiquitous	marker	endothelial cell, ventricular zone, germinal epithelium of ovary

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DICER1	8,268
DROSHA	6,846

Intra-cohort edges

A	B	Sources
DICER1	DROSHA	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DICER1	Q9UPY3	21
DROSHA	Q9NRR4	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
MicroRNA (miRNA) biogenesis	2	456.8×	3e-05	DICER1, DROSHA
tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis	1	1903.3×	0.002	DICER1
Small interfering RNA (siRNA) biogenesis	1	571.0×	0.004	DICER1
Regulation of MITF-M-dependent genes involved in apoptosis	1	317.2×	0.006	DICER1
Gene Silencing by RNA	1	178.4×	0.007	DROSHA
M-decay: degradation of maternal mRNAs by maternally stored factors	1	163.1×	0.007	DICER1
Gene expression (Transcription)	1	8.9×	0.109	DROSHA

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
miRNA metabolic process	2	1404.3×	1e-05	DICER1, DROSHA
pre-miRNA processing	2	1123.5×	1e-05	DICER1, DROSHA
positive regulation of Schwann cell differentiation	1	4213.0×	0.002	DICER1
peripheral nervous system myelin formation	1	2808.7×	0.002	DICER1
global gene silencing by mRNA cleavage	1	2808.7×	0.002	DICER1
regulation of miRNA metabolic process	1	2808.7×	0.002	DROSHA
tRNA decay	1	1685.2×	0.002	DICER1
negative regulation of Schwann cell proliferation	1	1203.7×	0.003	DICER1
siRNA processing	1	936.2×	0.003	DICER1
regulation of regulatory T cell differentiation	1	936.2×	0.003	DROSHA
RISC complex assembly	1	766.0×	0.003	DICER1
primary miRNA processing	1	648.1×	0.003	DROSHA
apoptotic DNA fragmentation	1	601.9×	0.003	DICER1
miRNA processing	1	526.6×	0.004	DICER1
nerve development	1	468.1×	0.004	DICER1
positive regulation of myelination	1	383.0×	0.004	DICER1
negative regulation of tumor necrosis factor-mediated signaling pathway	1	227.7×	0.007	DICER1
neuron projection morphogenesis	1	138.1×	0.010	DICER1
negative regulation of tumor necrosis factor production	1	125.8×	0.011	DICER1
regulation of inflammatory response	1	84.3×	0.015	DROSHA
defense response to Gram-negative bacterium	1	84.3×	0.015	DROSHA
rRNA processing	1	70.8×	0.017	DROSHA
defense response to Gram-positive bacterium	1	63.8×	0.018	DROSHA
negative regulation of gene expression	1	34.5×	0.031	DICER1
positive regulation of gene expression	1	19.4×	0.053	DROSHA
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	DICER1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bevacizumab, Dasatinib Anhydrous, Irinotecan, Sirolimus, Temozolomide.

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
DICER1	0	0
DROSHA	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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DICER1	3.1.26.3	ribonuclease III
DROSHA	3.1.26.3	ribonuclease III

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	2	DICER1, DROSHA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
DICER1	8	—
DROSHA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	8
Not specified	5
PHASE2	3
EARLY_PHASE1	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00179803	PHASE2	COMPLETED	Stem Cell Transplant for High Risk Central Nervous System (CNS) Tumors
NCT01217437	PHASE2	COMPLETED	Temozolomide and Irinotecan Hydrochloride With or Without Bevacizumab in Treating Young Patients With Recurrent or Refractory Medulloblastoma or CNS Primitive Neuroectodermal Tumors
NCT02095132	PHASE1/PHASE2	COMPLETED	Adavosertib and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT02596828	PHASE2	COMPLETED	Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma
NCT03500991	PHASE1	ACTIVE_NOT_RECRUITING	HER2-specific CAR T Cell Locoregional Immunotherapy for HER2-positive Recurrent/Refractory Pediatric CNS Tumors
NCT06193759	PHASE1	RECRUITING	Immunotherapy for Malignant Pediatric Brain Tumors Employing Adoptive Cellular Therapy (IMPACT)
NCT07087002	PHASE1	RECRUITING	GPC2-CAR T Cell Therapy for Relapsed or Refractory Medulloblastoma in Children and Young Adults
NCT07390539	PHASE1	NOT_YET_RECRUITING	B7-H3.CD28Z.CART in CNS Neoplasms
NCT00867178	PHASE1	COMPLETED	Vorinostat Combined With Isotretinoin and Chemotherapy in Treating Younger Patients With Embryonal Tumors of the Central Nervous System
NCT03434262	PHASE1	COMPLETED	SJDAWN: St. Jude Children’s Research Hospital Phase 1 Study Evaluating Molecularly-Driven Doublet Therapies for Children and Young Adults With Recurrent Brain Tumors
NCT03638167	PHASE1	COMPLETED	EGFR806-specific CAR T Cell Locoregional Immunotherapy for EGFR-positive Recurrent or Refractory Pediatric CNS Tumors
NCT03990597	PHASE1	WITHDRAWN	StrataXRT in Preventing Radiation Dermatitis in Pediatric Patients Undergoing Radiation Therapy to the Brain or Spinal Cord
NCT06942039	EARLY_PHASE1	RECRUITING	Pilot Study of IT Topotecan and Maintenance Chemotherapy for HR-EBTs in Children < 6 Years, Post Consolidation
NCT07017816	EARLY_PHASE1	RECRUITING	A Phase 0/1 Study of cDNA for TP53, Checkpoint Inhibition and Radiation in Children With Recurrent, Progressive or Refractory CNS Malignancies.
NCT03382158	Not specified	RECRUITING	International PPB/DICER1 Registry
NCT00565903	Not specified	COMPLETED	Elucidating the Genetic Basis of the Pleuropulmonary Blastoma (PPB) Familial Cancer Syndrome
NCT01063114	Not specified	COMPLETED	Proton Beam Radiotherapy for Medulloblastoma and Pineoblastoma
NCT01884194	Not specified	COMPLETED	Morphological Analysis of the Pineal Gland in Pediatric Retinoblastoma Patients Using Magnetic Resonance Imaging
NCT05934630	Not specified	TERMINATED	Testing Cerebrospinal Fluid for Cell-free Tumor DNA in Children, Adolescents, and Young Adults With Brain Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ETOPOSIDE PHOSPHATE	4	2
BEVACIZUMAB	4	1
ISOTRETINOIN	4	1
SONIDEGIB	4	1
ADAVOSERTIB	2	1