diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
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Summary
diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (MONDO:0858939) is a cancer with 14 cohort genes (13 CIViC-evidence somatic drivers; 16 ClinVar predisposition records) and 1 clinical trial. The dominant Reactome pathway is Impaired BRCA2 binding to PALB2 (3 cohort genes). Top therapeutic interventions include lutetium lu-177 vipivotide tetraxetan.
At a glance
- Classification: Cancer
- Cohort genes: 14
- ClinVar variants: 16
- Clinical trials: 1
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype |
| Mondo ID | MONDO:0858939 |
| DOID | DOID:0081277 |
| NCIT | C185467 |
| UMLS | C5669918 |
| MedGen | 1808288 |
| GARD | 0026635 |
| Is cancer (heuristic) | yes |
Data availability: 16 ClinVar variants.
Disease family
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 › 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
16 retrieved; paginated sample, class counts are floors:
8 uncertain significance, 6 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 12364 | NM_000546.6(TP53):c.844C>T (p.Arg282Trp) | TP53 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 510755 | NM_000075.4(CDK4):c.683+8A>T | CDK4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 219686 | NM_001042492.3(NF1):c.5225A>G (p.Asn1742Ser) | NF1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 662202 | NM_000535.7(PMS2):c.2534A>G (p.His845Arg) | PMS2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 543745 | NM_020975.6(RET):c.2657G>A (p.Arg886Gln) | RET | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 252906 | NM_004168.4(SDHA):c.155C>T (p.Ser52Phe) | SDHA | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 406566 | NM_000546.6(TP53):c.811G>A (p.Glu271Lys) | TP53 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 836167 | NM_004304.5(ALK):c.623T>C (p.Ile208Thr) | ALK | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2573117 | NM_000135.4(FANCA):c.1081A>G (p.Arg361Gly) | FANCA | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2573127 | NM_000135.4(FANCA):c.3659C>T (p.Pro1220Leu) | FANCA | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1315452 | NM_000142.5(FGFR3):c.328C>T (p.Arg110Trp) | FGFR3 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2572078 | NM_005896.4(IDH1):c.976T>C (p.Ser326Pro) | IDH1 | Uncertain significance | criteria provided, single submitter |
| 2573113 | NM_006618.5(KDM5B):c.1536C>G (p.His512Gln) | KDM5B | Uncertain significance | criteria provided, single submitter |
| 3370311 | NM_024675.4(PALB2):c.2586G>A (p.Lys862=) | PALB2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2577876 | NM_001321821.2(RAD51B):c.1275_1276dup (p.Ter426CysextTer?) | RAD51B | Uncertain significance | criteria provided, single submitter |
| 188438 | NM_000059.4(BRCA2):c.7563C>A (p.Ile2521=) | BRCA2 | Likely benign | reviewed by expert panel |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 0 · Orphanet: 97 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
Somatic driver evidence (intOGen + CIViC, cohort fanout)
| Gene | intOGen role | Cancer types | CIViC |
|---|---|---|---|
| SDHA | Act | CHRCC,HCC,LGGNOS | CIViC #5176 |
| BRCA2 | LoF | BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA | CIViC #7 |
| TP53 | LoF | ACC,ALL,AML,ANGS,ANSC,BCC,BL,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,EGC,ES,ESCA,ESCC,GB,GBC,GBM,GIST,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LNM,LUAD,LUSC,MBL,MEL,MLYM,MT,NBL,NETNOS,NHL,NPC,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PCM,PLMESO,PRAD,PRCC,PROSTATE,RCC,READ,SACA,SARCNOS,SCLC,SIC,SKCM,SKIN,SOFT_TISSUE,STAD,STOMACH,THYM,UCEC,UCS,UTUC,VULVA,WDTC,WT | CIViC #45 |
| CDK4 | LoF | MEL | CIViC #13 |
| PALB2 | LoF | OVT | CIViC #15013 |
| FANCA | Act | PRAD | CIViC #1810 |
| FGFR3 | Act | BLADDER,BLCA,HNSC,LUSC,PCM,PLMESO,UTUC | CIViC #23 |
| ALK | Act | BRCA,HCC,NBL,NSCLC,PROSTATE,SCLC | CIViC #1 |
| IDH1 | Act | AML,CHOL,GB,GBM,HCC,HGGNOS,LGGNOS,MBL,MEL,MT,OS,PAST,PCM,PRAD,SKCM | CIViC #26 |
| NF1 | LoF | ACC,ALL,AML,ANGS,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COADREAD,GB,GBM,GIST,HCC,HNSC,LGGNOS,LMS,LUAD,LUNG,LUSC,MEL,NBL,NSCLC,OVT,PAST,PGNG,PLMESO,RMS,SKCM,SOFT_TISSUE,STAD,THYM,UCS | CIViC #3867 |
| PMS2 | ambiguous | HCC | CIViC #4371 |
| RAD51B | CIViC #4763 | ||
| RET | Act | ANGS,MEL,NSCLC,PGNG,SOFT_TISSUE,WDTC | CIViC #42 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| SDHA | Orphanet:139411 | Carney triad |
| SDHA | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| SDHA | Orphanet:29072 | Hereditary pheochromocytoma-paraganglioma |
| SDHA | Orphanet:3208 | Isolated succinate-CoQ reductase deficiency |
| SDHA | Orphanet:44890 | Gastrointestinal stromal tumor |
| SDHA | Orphanet:97286 | Carney-Stratakis syndrome |
| BRCA2 | Orphanet:1331 | Familial prostate cancer |
| BRCA2 | Orphanet:1333 | Familial pancreatic carcinoma |
| BRCA2 | Orphanet:145 | Hereditary breast and/or ovarian cancer syndrome |
| BRCA2 | Orphanet:178 | Chordoma |
| BRCA2 | Orphanet:227535 | Hereditary breast cancer |
| BRCA2 | Orphanet:319462 | Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations |
| BRCA2 | Orphanet:440437 | Familial colorectal cancer Type X |
| BRCA2 | Orphanet:654 | Nephroblastoma |
| BRCA2 | Orphanet:667662 | Breast implant-associated anaplastic large cell lymphoma |
| BRCA2 | Orphanet:694963 | Inflammatory breast cancer |
| BRCA2 | Orphanet:70567 | Cholangiocarcinoma |
| BRCA2 | Orphanet:84 | Fanconi anemia |
| TP53 | Orphanet:1333 | Familial pancreatic carcinoma |
| TP53 | Orphanet:145 | Hereditary breast and/or ovarian cancer syndrome |
| TP53 | Orphanet:1501 | Adrenocortical carcinoma |
| TP53 | Orphanet:210159 | Adult hepatocellular carcinoma |
| TP53 | Orphanet:251576 | Gliosarcoma |
| TP53 | Orphanet:251579 | Giant cell glioblastoma |
| TP53 | Orphanet:251899 | Choroid plexus carcinoma |
| TP53 | Orphanet:2807 | Papilloma of choroid plexus |
| TP53 | Orphanet:293199 | Pleomorphic rhabdomyosarcoma |
| TP53 | Orphanet:3318 | Essential thrombocythemia |
| TP53 | Orphanet:524 | Li-Fraumeni syndrome |
| TP53 | Orphanet:52688 | Myelodysplastic syndrome |
| TP53 | Orphanet:585909 | B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2) |
| TP53 | Orphanet:667662 | Breast implant-associated anaplastic large cell lymphoma |
| TP53 | Orphanet:668 | Osteosarcoma |
| TP53 | Orphanet:67038 | B-cell chronic lymphocytic leukemia |
| TP53 | Orphanet:70573 | Small cell lung cancer |
| TP53 | Orphanet:96253 | Cushing disease |
| TP53 | Orphanet:99756 | Alveolar rhabdomyosarcoma |
| TP53 | Orphanet:99757 | Embryonal rhabdomyosarcoma |
| CDK4 | Orphanet:618 | Familial melanoma |
| CDK4 | Orphanet:99970 | Dedifferentiated liposarcoma |
| CDK4 | Orphanet:99971 | Well-differentiated liposarcoma |
| KDM5B | Orphanet:178469 | Autosomal dominant non-syndromic intellectual disability |
| KDM5B | Orphanet:88616 | Autosomal recessive non-syndromic intellectual disability |
| PALB2 | Orphanet:1333 | Familial pancreatic carcinoma |
| PALB2 | Orphanet:145 | Hereditary breast and/or ovarian cancer syndrome |
| PALB2 | Orphanet:178 | Chordoma |
| PALB2 | Orphanet:227535 | Hereditary breast cancer |
| PALB2 | Orphanet:84 | Fanconi anemia |
| FANCA | Orphanet:84 | Fanconi anemia |
| FGFR3 | Orphanet:15 | Achondroplasia |
Cohort genes → proteins
14 cohort genes, 14 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 14 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| SDHA | HGNC:10680 | ENSG00000073578 | P31040 | Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial | clinvar |
| BRCA2 | HGNC:1101 | ENSG00000139618 | P51587 | Breast cancer type 2 susceptibility protein | clinvar |
| TP53 | HGNC:11998 | ENSG00000141510 | P04637 | Cellular tumor antigen p53 | clinvar |
| CDK4 | HGNC:1773 | ENSG00000135446 | P11802 | Cyclin-dependent kinase 4 | clinvar |
| KDM5B | HGNC:18039 | ENSG00000117139 | Q9UGL1 | Lysine-specific demethylase 5B | clinvar |
| PALB2 | HGNC:26144 | ENSG00000083093 | Q86YC2 | Partner and localizer of BRCA2 | clinvar |
| FANCA | HGNC:3582 | ENSG00000187741 | O15360 | Fanconi anemia group A protein | clinvar |
| FGFR3 | HGNC:3690 | ENSG00000068078 | P22607 | Fibroblast growth factor receptor 3 | clinvar |
| ALK | HGNC:427 | ENSG00000171094 | Q9UM73 | ALK tyrosine kinase receptor | clinvar |
| IDH1 | HGNC:5382 | ENSG00000138413 | O75874 | Isocitrate dehydrogenase [NADP] cytoplasmic | clinvar |
| NF1 | HGNC:7765 | ENSG00000196712 | P21359 | Neurofibromin | clinvar |
| PMS2 | HGNC:9122 | ENSG00000122512 | P54278 | Mismatch repair endonuclease PMS2 | clinvar |
| RAD51B | HGNC:9822 | ENSG00000182185 | O15315 | DNA repair protein RAD51 homolog 2 | clinvar |
| RET | HGNC:9967 | ENSG00000165731 | P07949 | Proto-oncogene tyrosine-protein kinase receptor Ret | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| SDHA | Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial | Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q). |
| BRCA2 | Breast cancer type 2 susceptibility protein | Involved in double-strand break repair and/or homologous recombination. |
| TP53 | Cellular tumor antigen p53 | Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence. |
| CDK4 | Cyclin-dependent kinase 4 | Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. |
| KDM5B | Lysine-specific demethylase 5B | Histone demethylase that demethylates ‘Lys-4’ of histone H3, thereby playing a central role in histone code. |
| PALB2 | Partner and localizer of BRCA2 | Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks. |
| FANCA | Fanconi anemia group A protein | DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function. |
| FGFR3 | Fibroblast growth factor receptor 3 | Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. |
| ALK | ALK tyrosine kinase receptor | Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. |
| IDH1 | Isocitrate dehydrogenase [NADP] cytoplasmic | Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase. |
| NF1 | Neurofibromin | Stimulates the GTPase activity of Ras. |
| PMS2 | Mismatch repair endonuclease PMS2 | Component of the post-replicative DNA mismatch repair system (MMR). |
| RAD51B | DNA repair protein RAD51 homolog 2 | Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. |
| RET | Proto-oncogene tyrosine-protein kinase receptor Ret | Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,… |
Protein-family classification
Druggable: 5 · Difficult: 3 · Unknown: 6 · Druggable fraction: 0.36
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 |
|---|---|---|---|
| Kinase | 4 | 7.9× | 0.006 |
| Scaffold/PPI | 1 | 1.2× | 0.881 |
| Transcription factor | 2 | 1.2× | 0.881 |
| Enzyme (other) | 1 | 0.9× | 0.881 |
| Other/Unknown | 6 | 0.8× | 0.893 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| SDHA | Other/Unknown | no | FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd | |
| BRCA2 | Other/Unknown | no | BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1 | |
| TP53 | Transcription factor | no | p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn | |
| CDK4 | Kinase | yes | 2.7.11.22 | Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf |
| KDM5B | Transcription factor | no | 1.14.11.67 | ARID_dom, Znf_PHD, JmjC_dom |
| PALB2 | Scaffold/PPI | no | WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf | |
| FANCA | Other/Unknown | no | FANCA, Fanconi_A_N, Fanconi_A_C | |
| FGFR3 | Kinase | yes | 2.7.10.1 | Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2 |
| ALK | Kinase | yes | 2.7.10.1 | Prot_kinase_dom, MAM_dom, Ser-Thr/Tyr_kinase_cat_dom |
| IDH1 | Enzyme (other) | yes | 1.1.1.42 | Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom |
| NF1 | Other/Unknown | no | CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot | |
| PMS2 | Other/Unknown | no | MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr | |
| RAD51B | Other/Unknown | no | AAA+_ATPase, Rad51_C, DNA_recomb/repair_RecA-like | |
| RET | Kinase | yes | 2.7.10.1 | Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom |
Expression context
Cohort genes with no expression data: 0.
13 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) | 14 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| male germ line stem cell (sensu Vertebrata) in testis | 4 |
| ventricular zone | 4 |
| secondary oocyte | 2 |
| ganglionic eminence | 2 |
| left testis | 2 |
| male germ cell | 2 |
| sperm | 2 |
| buccal mucosa cell | 2 |
| adrenal tissue | 2 |
| apex of heart | 1 |
| heart left ventricle | 1 |
| mucosa of transverse colon | 1 |
| tendon of biceps brachii | 1 |
| embryo | 1 |
| oocyte | 1 |
| right testis | 1 |
| skin of hip | 1 |
| upper arm skin | 1 |
| upper leg skin | 1 |
| corpus epididymis | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| SDHA | 143 | ubiquitous | marker | apex of heart, heart left ventricle, mucosa of transverse colon |
| BRCA2 | 184 | ubiquitous | marker | male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone |
| TP53 | 223 | ubiquitous | marker | ventricular zone, ganglionic eminence, tendon of biceps brachii |
| CDK4 | 138 | ubiquitous | marker | embryo, ganglionic eminence, ventricular zone |
| KDM5B | 272 | ubiquitous | marker | sperm, male germ cell, left testis |
| PALB2 | 232 | ubiquitous | yes | secondary oocyte, buccal mucosa cell, oocyte |
| FANCA | 185 | ubiquitous | marker | right testis, ventricular zone, left testis |
| FGFR3 | 262 | broad | marker | upper leg skin, skin of hip, upper arm skin |
| ALK | 181 | broad | marker | sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis |
| IDH1 | 294 | ubiquitous | marker | corpus epididymis, jejunal mucosa, adrenal tissue |
| NF1 | 283 | ubiquitous | marker | colonic epithelium, calcaneal tendon, adrenal tissue |
| PMS2 | 143 | ubiquitous | marker | thymus, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis |
| RAD51B | 193 | ubiquitous | marker | sural nerve, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis |
| RET | 193 | broad | marker | substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta |
Protein interactions among cohort
Intra-cohort edges: 9.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| TP53 | 22,736 |
| CDK4 | 8,412 |
| SDHA | 6,141 |
| PALB2 | 5,641 |
| NF1 | 5,540 |
| IDH1 | 5,464 |
| BRCA2 | 4,839 |
| ALK | 4,792 |
| FGFR3 | 4,510 |
| RET | 4,203 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| ALK | RET | intact |
| BRCA2 | PALB2 | biogrid_interaction, intact, string_interaction |
| BRCA2 | PMS2 | string_interaction |
| BRCA2 | RAD51B | string_interaction |
| BRCA2 | TP53 | string_interaction |
| IDH1 | TP53 | string_interaction |
| NF1 | RET | string_interaction |
| NF1 | TP53 | string_interaction |
| PALB2 | RAD51B | string_interaction |
Structural data
PDB: 14 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| TP53 | P04637 | 313 |
| ALK | Q9UM73 | 79 |
| IDH1 | O75874 | 61 |
| KDM5B | Q9UGL1 | 56 |
| RET | P07949 | 34 |
| NF1 | P21359 | 26 |
| CDK4 | P11802 | 15 |
| FGFR3 | P22607 | 15 |
| BRCA2 | P51587 | 14 |
| PMS2 | P54278 | 9 |
| FANCA | O15360 | 6 |
| SDHA | P31040 | 5 |
| RAD51B | O15315 | 5 |
| PALB2 | Q86YC2 | 4 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 177. Enrichment computed across 14 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Impaired BRCA2 binding to PALB2 | 3 | 97.9× | 2e-04 | BRCA2, PALB2, RAD51B |
| Defective homologous recombination repair (HRR) due to BRCA1 loss of function | 3 | 90.6× | 2e-04 | BRCA2, PALB2, RAD51B |
| Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function | 3 | 90.6× | 2e-04 | BRCA2, PALB2, RAD51B |
| Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function | 3 | 90.6× | 2e-04 | BRCA2, PALB2, RAD51B |
| Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) | 3 | 84.4× | 2e-04 | BRCA2, PALB2, RAD51B |
| Homologous DNA Pairing and Strand Exchange | 3 | 81.6× | 2e-04 | BRCA2, PALB2, RAD51B |
| Resolution of D-loop Structures through Holliday Junction Intermediates | 3 | 64.4× | 3e-04 | BRCA2, PALB2, RAD51B |
| HDR through Homologous Recombination (HRR) | 3 | 40.8× | 0.001 | BRCA2, PALB2, RAD51B |
| t(4;14) translocations of FGFR3 | 1 | 815.7× | 0.009 | FGFR3 |
| Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate | 1 | 815.7× | 0.009 | IDH1 |
| Signaling by FGFR3 fusions in cancer | 1 | 815.7× | 0.009 | FGFR3 |
| Drug resistance of ALK mutants | 1 | 815.7× | 0.009 | ALK |
| ASP-3026-resistant ALK mutants | 1 | 815.7× | 0.009 | ALK |
| NVP-TAE684-resistant ALK mutants | 1 | 815.7× | 0.009 | ALK |
| alectinib-resistant ALK mutants | 1 | 815.7× | 0.009 | ALK |
| brigatinib-resistant ALK mutants | 1 | 815.7× | 0.009 | ALK |
| ceritinib-resistant ALK mutants | 1 | 815.7× | 0.009 | ALK |
| crizotinib-resistant ALK mutants | 1 | 815.7× | 0.009 | ALK |
| lorlatinib-resistant ALK mutants | 1 | 815.7× | 0.009 | ALK |
| Loss of function of TP53 in cancer due to loss of tetramerization ability | 1 | 815.7× | 0.009 | TP53 |
| Oncogene Induced Senescence | 2 | 48.0× | 0.009 | TP53, CDK4 |
| Meiosis | 2 | 40.8× | 0.009 | BRCA2, CDK4 |
| Presynaptic phase of homologous DNA pairing and strand exchange | 2 | 38.8× | 0.009 | BRCA2, RAD51B |
| RAF/MAP kinase cascade | 3 | 13.1× | 0.010 | FGFR3, NF1, RET |
| NADPH regeneration | 1 | 407.9× | 0.014 | IDH1 |
| Defective Mismatch Repair Associated With MLH1 | 1 | 407.9× | 0.014 | PMS2 |
| Defective Mismatch Repair Associated With PMS2 | 1 | 407.9× | 0.014 | PMS2 |
| Regulation of TP53 Expression | 1 | 407.9× | 0.014 | TP53 |
| Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 | 1 | 407.9× | 0.014 | CDK4 |
| Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 | 1 | 407.9× | 0.014 | CDK4 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| female gonad development | 3 | 172.0× | 2e-04 | BRCA2, FANCA, IDH1 |
| positive regulation of extrinsic apoptotic signaling pathway in absence of ligand | 2 | 218.9× | 0.005 | NF1, RET |
| negative regulation of neuroblast proliferation | 2 | 172.0× | 0.005 | TP53, NF1 |
| inner cell mass cell proliferation | 2 | 141.6× | 0.005 | BRCA2, PALB2 |
| response to X-ray | 2 | 126.7× | 0.005 | BRCA2, TP53 |
| negative regulation of stem cell proliferation | 2 | 120.4× | 0.005 | TP53, NF1 |
| double-strand break repair via homologous recombination | 3 | 33.4× | 0.005 | BRCA2, PALB2, RAD51B |
| MAPK cascade | 3 | 32.8× | 0.005 | FGFR3, NF1, RET |
| positive regulation of G2/M transition of mitotic cell cycle | 2 | 86.0× | 0.009 | CDK4, RAD51B |
| response to gamma radiation | 2 | 83.0× | 0.009 | BRCA2, TP53 |
| tricarboxylic acid cycle | 2 | 73.0× | 0.009 | SDHA, IDH1 |
| intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator | 2 | 70.8× | 0.009 | BRCA2, TP53 |
| negative regulation of fibroblast proliferation | 2 | 70.8× | 0.009 | TP53, NF1 |
| embryonic organ development | 2 | 68.8× | 0.009 | TP53, PALB2 |
| positive regulation of mast cell apoptotic process | 1 | 1203.7× | 0.010 | NF1 |
| regulation of glial cell differentiation | 1 | 1203.7× | 0.010 | NF1 |
| negative regulation of developmental growth | 1 | 1203.7× | 0.010 | FGFR3 |
| negative regulation of helicase activity | 1 | 1203.7× | 0.010 | TP53 |
| regulation of phospholipid catabolic process | 1 | 1203.7× | 0.010 | IDH1 |
| cellular response to actinomycin D | 1 | 1203.7× | 0.010 | TP53 |
| observational learning | 1 | 1203.7× | 0.010 | NF1 |
| regulation of intrinsic apoptotic signaling pathway by p53 class mediator | 1 | 1203.7× | 0.010 | TP53 |
| negative regulation of G1 to G0 transition | 1 | 1203.7× | 0.010 | TP53 |
| regulation of estradiol secretion | 1 | 1203.7× | 0.010 | KDM5B |
| cellular response to ionizing radiation | 2 | 58.7× | 0.010 | BRCA2, TP53 |
| fibroblast proliferation | 2 | 56.0× | 0.010 | TP53, NF1 |
| nucleotide-excision repair | 2 | 54.7× | 0.010 | BRCA2, TP53 |
| somitogenesis | 2 | 53.5× | 0.010 | TP53, PALB2 |
| neuroblast proliferation | 2 | 52.3× | 0.010 | TP53, NF1 |
| DNA damage response, signal transduction by p53 class mediator | 2 | 51.2× | 0.010 | BRCA2, TP53 |
Therapeutics
Drug target analysis
Approved (phase 4): 7 · Phase ≥3: 8 · Phased (≥1): 8 · Undrugged: 6
Druggability breadth: 9 of 14 evidence-associated genes (64%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| SDHA | LINEZOLID |
| TP53 | NITROFURANTOIN |
| CDK4 | PALBOCICLIB |
| FGFR3 | PONATINIB |
| ALK | CERITINIB |
| IDH1 | ENASIDENIB |
| RET | PONATINIB |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| TP53 | 196 | 4 |
| RET | 135 | 4 |
| FGFR3 | 64 | 4 |
| ALK | 61 | 4 |
| CDK4 | 56 | 4 |
| IDH1 | 10 | 4 |
| KDM5B | 2 | 3 |
| SDHA | 1 | 4 |
| BRCA2 | 0 | 0 |
| PALB2 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| LINEZOLID | 4 | SDHA |
| NITROFURANTOIN | 4 | TP53 |
| DIOSMIN | 4 | TP53 |
| VERTEPORFIN | 4 | TP53 |
| CANDESARTAN CILEXETIL | 4 | TP53 |
| DIENESTROL | 4 | TP53 |
| CLOTRIMAZOLE | 4 | TP53 |
| COLCHICINE | 4 | TP53 |
| NABUMETONE | 4 | TP53 |
| SALMETEROL XINAFOATE | 4 | TP53 |
| AMIODARONE HYDROCHLORIDE | 4 | TP53 |
| FURAZOLIDONE | 4 | TP53 |
| AMOXAPINE | 4 | TP53 |
| RALOXIFENE HYDROCHLORIDE | 4 | TP53 |
| NICARDIPINE HYDROCHLORIDE | 4 | TP53 |
| SULCONAZOLE NITRATE | 4 | TP53 |
| PYRITHIONE ZINC | 4 | TP53 |
| LACTIC ACID | 4 | TP53 |
| OXYMETHOLONE | 4 | TP53 |
| CHLOROXINE | 4 | TP53 |
| PROPIOLACTONE | 4 | TP53 |
| CLOMIPRAMINE HYDROCHLORIDE | 4 | TP53 |
| PHENYL AMINOSALICYLATE | 4 | TP53 |
| THIORIDAZINE HYDROCHLORIDE | 4 | TP53 |
| AMITRIPTYLINE HYDROCHLORIDE | 4 | TP53 |
| ETHOPROPAZINE HYDROCHLORIDE | 4 | TP53 |
| MECHLORETHAMINE HYDROCHLORIDE | 4 | TP53 |
| ECONAZOLE NITRATE | 4 | TP53 |
| TRIFLUPROMAZINE HYDROCHLORIDE | 4 | TP53 |
| PROCHLORPERAZINE EDISYLATE | 4 | TP53 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 6.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| ALK | 1,815 | Binding:1801, Functional:13, ADMET:1 |
| RET | 1,586 | Binding:1573, Functional:10, ADMET:3 |
| CDK4 | 1,142 | Binding:1086, Functional:53, ADMET:2, Toxicity:1 |
| FGFR3 | 975 | Binding:948, Functional:18, ADMET:9 |
| TP53 | 869 | Binding:775, ADMET:83, Functional:10, Toxicity:1 |
| IDH1 | 488 | Binding:475, Functional:12, ADMET:1 |
| KDM5B | 146 | Binding:146 |
| SDHA | 3 | Binding:3 |
| PMS2 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| CDK4 | 2.7.11.22 | cyclin-dependent kinase |
| KDM5B | 1.14.11.67 | [histone H3]-trimethyl-L-lysine4 demethylase |
| FGFR3 | 2.7.10.1 | receptor protein-tyrosine kinase |
| ALK | 2.7.10.1 | receptor protein-tyrosine kinase |
| IDH1 | 1.1.1.42 | isocitrate dehydrogenase (NADP+) |
| RET | 2.7.10.1 | receptor protein-tyrosine kinase |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| TP53 | 869 |
| CDK4 | 1,142 |
| KDM5B | 146 |
| FGFR3 | 975 |
| ALK | 1,815 |
| IDH1 | 488 |
| RET | 1,586 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 14; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Drug repurposing candidates
30 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.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| LINEZOLID | 4 | SDHA |
| NITROFURANTOIN | 4 | TP53 |
| DIOSMIN | 4 | TP53 |
| VERTEPORFIN | 4 | TP53 |
| CANDESARTAN CILEXETIL | 4 | TP53 |
| DIENESTROL | 4 | TP53 |
| CLOTRIMAZOLE | 4 | TP53 |
| COLCHICINE | 4 | TP53 |
| NABUMETONE | 4 | TP53 |
| SALMETEROL XINAFOATE | 4 | TP53 |
| AMIODARONE HYDROCHLORIDE | 4 | TP53 |
| FURAZOLIDONE | 4 | TP53 |
| AMOXAPINE | 4 | TP53 |
| RALOXIFENE HYDROCHLORIDE | 4 | TP53 |
| NICARDIPINE HYDROCHLORIDE | 4 | TP53 |
| SULCONAZOLE NITRATE | 4 | TP53 |
| PYRITHIONE ZINC | 4 | TP53 |
| LACTIC ACID | 4 | TP53 |
| OXYMETHOLONE | 4 | TP53 |
| CHLOROXINE | 4 | TP53 |
| PROPIOLACTONE | 4 | TP53 |
| CLOMIPRAMINE HYDROCHLORIDE | 4 | TP53 |
| PHENYL AMINOSALICYLATE | 4 | TP53 |
| THIORIDAZINE HYDROCHLORIDE | 4 | TP53 |
| AMITRIPTYLINE HYDROCHLORIDE | 4 | TP53 |
| ETHOPROPAZINE HYDROCHLORIDE | 4 | TP53 |
| MECHLORETHAMINE HYDROCHLORIDE | 4 | TP53 |
| ECONAZOLE NITRATE | 4 | TP53 |
| TRIFLUPROMAZINE HYDROCHLORIDE | 4 | TP53 |
| PROCHLORPERAZINE EDISYLATE | 4 | TP53 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 7 | SDHA, TP53, CDK4, FGFR3, ALK, IDH1, RET |
| B | Phased (≥1) drug, not yet approved | 1 | KDM5B |
| C | Druggable family + PDB, no drug | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 6 | BRCA2, PALB2, FANCA, NF1, PMS2, RAD51B |
Undrugged target profiles
6 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| BRCA2 | 0 | — |
| PALB2 | 0 | — |
| FANCA | 0 | — |
| NF1 | 0 | — |
| PMS2 | 1 | — |
| RAD51B | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 1.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| PHASE1 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT07223034 | PHASE1 | RECRUITING | A Study of 177Lu-PSMA-617 in People With Gliomas |
Drugs tested across these trials (top 30)
| Molecule | Max phase | Trials referencing |
|---|---|---|
| LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN | 4 | 1 |
| CHEMBL4228794 | 0 | 1 |