◎ Sugi Atlas

Atlas / Disease / Pilocytic astrocytoma

Pilocytic astrocytoma

disease
On this page

Also known as astrocytoma, benignastrocytoma, pilocytic, benigngrade I astrocytic neoplasmgrade I astrocytic tumorgrade I astrocytic tumourgrade I astrocytoma

Summary

Pilocytic astrocytoma (MONDO:0016691) is a disease with 13 cohort genes (333 GWAS associations across 4 studies) and 10 clinical trials. The dominant Reactome pathway is Impaired BRCA2 binding to PALB2 (3 cohort genes). Molecularly, BRAF V600E confers sensitivity to Dabrafenib + Trametinib in Pilocytic Astrocytoma (CIViC Level A); 7 further subtype–drug associations are mapped below. Top therapeutic interventions include dabrafenib, tovorafenib, and trametinib.

At a glance

  • Prevalence: 1-9 / 1 000 000 (United States) [Orphanet-validated]
  • Cohort genes: 13
  • GWAS associations: 333
  • ClinVar variants: 20
  • Clinical trials: 10
  • Precision-medicine evidence (CIViC): 8 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

TypeClassValueGeographyValidation
Annual incidence1-9 / 1 000 0000.36United StatesValidated

Identifiers

Disease identifiers

FieldValue
Canonical namepilocytic astrocytoma
Mondo IDMONDO:0016691
Orphanet251612
DOIDDOID:4851
NCITC4047
SNOMED CT763865009
UMLSC0334583
MedGen87271
GARD0009808
Is cancer (heuristic)no

Also known as: astrocytoma, benign · astrocytoma, pilocytic, benign · grade I astrocytic neoplasm · grade I astrocytic tumor · grade I astrocytic tumour · grade I astrocytoma · pilocytic astrocytoma

Data availability: 20 ClinVar variants · 333 GWAS associations (4 studies) · 7 cell lines · 42 intOGen driver records.

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 › pilocytic astrocytoma

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

Subtypes (4): cerebellar pilocytic astrocytoma, childhood pilocytic astrocytoma, pilomyxoid astrocytoma, pilocytic astrocytoma with histological features of anaplasia

Genetics & variants

GWAS landscape

333 GWAS associations across 4 studies. Top hits map to 32 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs5343826663e-09MAPRE1P2 - RPL31P31?8.29
rs1919459538e-09OLA1?7.39
rs1425416732e-08LINC02713?6.66
rs1909275272e-08LINC02473 - HNRNPA1P65?6.05
rs1889643353e-08KLF3-AS1?8.4
rs610704914e-08Y_RNA - CARS1P2?3.23
rs1914974524e-08OLA1?7.86
rs5736875e-08CDKN2B-AS1?1.3
rs619034685e-08NTM?3.08
rs5531772977e-08MAPRE1P2 - RPL31P31?10.62
rs353242028e-08RPS17P11 - MFSD4BP1?1.7
rs730925449e-08SRSF8CP - TNS3?1.95
rs100667581e-07LINC02208?1.32
rs790824032e-07Y_RNA - CARS1P2?2.87
rs1388822832e-07RPLP0P9 - LINC01947?8.81
rs1452058472e-07TMEM232?3.47
rs28117132e-07CDKN2B-AS1?1.33
rs1915197833e-07LINC02713 - CNTN5?5.92
rs5711240103e-07CEP128?4.85
rs1438730703e-07RPH3A?5.83
rs1124995313e-07SESN1?2.36
rs1448748774e-07AP1G1?6.94
rs5495707724e-07OPCML?6.34
rs1123394994e-07SNAP23?1.57
rs1405099124e-07LMO7-AS1, LMO7?3.13
rs1468157294e-07WWOX?6.76
rs5356699835e-07PCBP2?7.44
rs24847565e-07MACF1?0.61
rs37428286e-07ZFYVE1?1.28
rs802167177e-07MANEA?1.84

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST90296470Foss-Skiftesvik J20239367,183Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
GCST90296480Foss-Skiftesvik J20239367,183Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
GCST90296469Foss-Skiftesvik J20237707,183Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.
GCST90296479Foss-Skiftesvik J20237707,183Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding0
Tier 2: splice/UTR3
Tier 3: regulatory0
Tier 4: intronic/intergenic47

MAF distribution

BucketVariants
common (>=0.05)22
low_freq (0.01-0.05)0
rare (<0.01)0
unknown28

Functional consequences

ConsequenceCount
intron_variant35
intergenic_variant11
3_prime_UTR_variant2
non_coding_transcript_exon_variant1
5_prime_UTR_variant1

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs534382666433735687G>A,Tintergenic_variantMAPRE1P2 - RPL31P313e-09Tier 4: intronic/intergenic
rs1919459532174228248A>G,Tintron_variantOLA18e-09Tier 4: intronic/intergenic
rs1425416731197941768A>Gintron_variantLINC027132e-08Tier 4: intronic/intergenic
rs190927527424765988T>Cintergenic_variantLINC02473 - HNRNPA1P652e-08Tier 4: intronic/intergenic
rs188964335438632512C>Tintron_variantKLF3-AS13e-08Tier 4: intronic/intergenic
rs610704918114490512G>A0.05intron_variantY_RNA - CARS1P24e-08Tier 4: intronic/intergenic
rs1914974522174119051C>Tintron_variantOLA14e-08Tier 4: intronic/intergenic
rs573687922011643G>A0.05intron_variantCDKN2B-AS15e-08Tier 4: intronic/intergenic
rs6190346811131990671A>G0.05intron_variantNTM5e-08Tier 4: intronic/intergenic
rs553177297433584822T>Gintron_variantMAPRE1P2 - RPL31P317e-08Tier 4: intronic/intergenic
rs35324202552471140C>T0.05intergenic_variantRPS17P11 - MFSD4BP18e-08Tier 4: intronic/intergenic
rs73092544747058600A>G0.05intron_variantSRSF8CP - TNS39e-08Tier 4: intronic/intergenic
rs100667585118467354C>G,T0.05intron_variantLINC022081e-07Tier 4: intronic/intergenic
rs790824038114365676C>G0.05intron_variantY_RNA - CARS1P22e-07Tier 4: intronic/intergenic
rs1388822835166405436T>A,C,Gintergenic_variantRPLP0P9 - LINC019472e-07Tier 4: intronic/intergenic
rs1452058475110712395A>Gintron_variantTMEM2322e-07Tier 4: intronic/intergenic
rs2811713921999329G>A,T0.05intron_variantCDKN2B-AS12e-07Tier 4: intronic/intergenic
rs1915197831198064894A>Gintron_variantLINC02713 - CNTN53e-07Tier 4: intronic/intergenic
rs5711240101480891397T>Cintron_variantCEP1283e-07Tier 4: intronic/intergenic
rs14387307012112775492G>Aintergenic_variantRPH3A3e-07Tier 4: intronic/intergenic
rs1124995316108984907A>G0.053_prime_UTR_variantSESN13e-07Tier 2: splice/UTR
rs1448748771671777661G>A,C,Tnon_coding_transcript_exon_variantAP1G14e-07Tier 4: intronic/intergenic
rs54957077211132713485C>Tintron_variantOPCML4e-07Tier 4: intronic/intergenic
rs1123394991542493350C>A0.05intergenic_variantSNAP234e-07Tier 4: intronic/intergenic
rs1405099121375632535A>Gintron_variantLMO7-AS1, LMO74e-07Tier 4: intronic/intergenic
rs1468157291678537671G>Aintron_variantWWOX4e-07Tier 4: intronic/intergenic
rs5356699831253453654G>Aintron_variantPCBP25e-07Tier 4: intronic/intergenic
rs2484756139249712A>C,G,T0.05intron_variantMACF15e-07Tier 4: intronic/intergenic
rs37428281473024599C>A,G,T0.055_prime_UTR_variantZFYVE16e-07Tier 2: splice/UTR
rs80216717695606825G>A0.053_prime_UTR_variantMANEA7e-07Tier 2: splice/UTR

ClinVar germline variants

20 retrieved; paginated sample, class counts are floors:

11 conflicting classifications of pathogenicity, 4 uncertain significance, 2 pathogenic, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVarVariant (HGVS)GeneClassificationReview
12593NM_004985.5(KRAS):c.37G>C (p.Gly13Arg)KRASPathogeniccriteria provided, single submitter
5293NM_001048174.2(MUTYH):c.452A>G (p.Tyr151Cys)MUTYHPathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
5294NM_001048174.2(MUTYH):c.1103G>A (p.Gly368Asp)MUTYHPathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
590842NM_001042492.3(NF1):c.6166A>T (p.Lys2056Ter)NF1Pathogeniccriteria provided, multiple submitters, no conflicts
620629NM_144997.7(FLCN):c.872-1G>TFLCNLikely pathogeniccriteria provided, multiple submitters, no conflicts
156187NM_007294.4(BRCA1):c.2456C>G (p.Ser819Cys)BRCA1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
523689NM_007294.4(BRCA1):c.4358-2725T>CBRCA1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
1371106NM_000059.4(BRCA2):c.66A>C (p.Ala22=)BRCA2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
38211NM_000059.4(BRCA2):c.9104A>C (p.Tyr3035Ser)BRCA2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
51448NM_000059.4(BRCA2):c.3310A>C (p.Thr1104Pro)BRCA2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
51479NM_000059.4(BRCA2):c.3503T>A (p.Met1168Lys)BRCA2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
52024NM_000059.4(BRCA2):c.6172T>A (p.Phe2058Ile)BRCA2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
41765NM_001048174.2(MUTYH):c.841C>T (p.Arg281Cys)MUTYHConflicting classifications of pathogenicitycriteria provided, conflicting classifications
225853NM_024675.4(PALB2):c.1478C>T (p.Pro493Leu)PALB2Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
136098NM_020975.6(RET):c.1344C>G (p.Asn448Lys)RETConflicting classifications of pathogenicitycriteria provided, conflicting classifications
142601NM_004168.4(SDHA):c.91C>T (p.Arg31Ter)SDHAConflicting classifications of pathogenicitycriteria provided, conflicting classifications
3623617NM_007294.4(BRCA1):c.2555T>G (p.Leu852Arg)BRCA1Uncertain significancecriteria provided, multiple submitters, no conflicts
41754NM_001048174.2(MUTYH):c.1336C>T (p.Arg446Cys)MUTYHUncertain significancecriteria provided, multiple submitters, no conflicts
4687849NM_134424.4(RAD52):c.84+1G>ARAD52Uncertain significancecriteria provided, single submitter
4687850NM_003579.4(RAD54L):c.1759C>T (p.Arg587Trp)RAD54LUncertain significancecriteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 96 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
KRASOrphanet:1333Familial pancreatic carcinoma
KRASOrphanet:1340Cardiofaciocutaneous syndrome
KRASOrphanet:144Lynch syndrome
KRASOrphanet:146Differentiated thyroid carcinoma
KRASOrphanet:2396Encephalocraniocutaneous lipomatosis
KRASOrphanet:251615Pilomyxoid astrocytoma
KRASOrphanet:2612Linear nevus sebaceus syndrome
KRASOrphanet:268114RAS-associated autoimmune leukoproliferative disease
KRASOrphanet:3339Oculoectodermal syndrome
KRASOrphanet:648Noonan syndrome
KRASOrphanet:86834Juvenile myelomonocytic leukemia
BRAFOrphanet:1340Cardiofaciocutaneous syndrome
BRAFOrphanet:146Differentiated thyroid carcinoma
BRAFOrphanet:251615Pilomyxoid astrocytoma
BRAFOrphanet:389Langerhans cell histiocytosis
BRAFOrphanet:500Noonan syndrome with multiple lentigines
BRAFOrphanet:54595Craniopharyngioma
BRAFOrphanet:58017Classic hairy cell leukemia
BRAFOrphanet:626Large/giant congenital melanocytic nevus
BRAFOrphanet:648Noonan syndrome
BRAFOrphanet:840Syringocystadenoma papilliferum
BRAFOrphanet:96253Cushing disease
FGFR1Orphanet:168953Myeloid/lymphoid neoplasm associated with FGFR1 rearrangement
FGFR1Orphanet:2117Hartsfield syndrome
FGFR1Orphanet:220386Semilobar holoprosencephaly
FGFR1Orphanet:2396Encephalocraniocutaneous lipomatosis
FGFR1Orphanet:251576Gliosarcoma
FGFR1Orphanet:251579Giant cell glioblastoma
FGFR1Orphanet:251615Pilomyxoid astrocytoma
FGFR1Orphanet:2645Osteoglosphonic dysplasia
FGFR1Orphanet:280200Microform holoprosencephaly
FGFR1Orphanet:314950Primary hypereosinophilic syndrome
FGFR1Orphanet:3157Septo-optic dysplasia spectrum
FGFR1Orphanet:3366Non-syndromic metopic craniosynostosis
FGFR1Orphanet:432Normosmic congenital hypogonadotropic hypogonadism
FGFR1Orphanet:478Kallmann syndrome
FGFR1Orphanet:93258Pfeiffer syndrome type 1
FGFR1Orphanet:93924Lobar holoprosencephaly
FGFR1Orphanet:99798Oligodontia
SDHAOrphanet:139411Carney triad
SDHAOrphanet:154Familial isolated dilated cardiomyopathy
SDHAOrphanet:29072Hereditary pheochromocytoma-paraganglioma
SDHAOrphanet:3208Isolated succinate-CoQ reductase deficiency
SDHAOrphanet:44890Gastrointestinal stromal tumor
SDHAOrphanet:97286Carney-Stratakis syndrome
BRCA1Orphanet:1331Familial prostate cancer
BRCA1Orphanet:1333Familial pancreatic carcinoma
BRCA1Orphanet:145Hereditary breast and/or ovarian cancer syndrome
BRCA1Orphanet:168829Primary peritoneal carcinoma
BRCA1Orphanet:227535Hereditary breast cancer

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

SubsetGenes
civic_only2
multi_evidence11

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
KRASHGNC:6407ENSG00000133703P01116GTPase KRasclinvar,civic_evidence
BRAFHGNC:1097ENSG00000157764P15056Serine/threonine-protein kinase B-rafcivic_evidence
FGFR1HGNC:3688ENSG00000077782P11362Fibroblast growth factor receptor 1civic_evidence
SDHAHGNC:10680ENSG00000073578P31040Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrialclinvar
BRCA1HGNC:1100ENSG00000012048P38398Breast cancer type 1 susceptibility proteinclinvar
BRCA2HGNC:1101ENSG00000139618P51587Breast cancer type 2 susceptibility proteinclinvar
PALB2HGNC:26144ENSG00000083093Q86YC2Partner and localizer of BRCA2clinvar
FLCNHGNC:27310ENSG00000154803Q8NFG4Folliculinclinvar
MUTYHHGNC:7527ENSG00000132781Q9UIF7Adenine DNA glycosylaseclinvar
NF1HGNC:7765ENSG00000196712P21359Neurofibrominclinvar
RAD52HGNC:9824ENSG00000002016P43351DNA repair protein RAD52 homologclinvar
RAD54LHGNC:9826ENSG00000085999Q92698DNA repair and recombination protein RAD54-likeclinvar
RETHGNC:9967ENSG00000165731P07949Proto-oncogene tyrosine-protein kinase receptor Retclinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
KRASGTPase KRasRas proteins bind GDP/GTP and possess intrinsic GTPase activity.
BRAFSerine/threonine-protein kinase B-rafProtein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
FGFR1Fibroblast growth factor receptor 1Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
SDHASuccinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrialFlavoprotein (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).
BRCA1Breast cancer type 1 susceptibility proteinE3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
BRCA2Breast cancer type 2 susceptibility proteinInvolved in double-strand break repair and/or homologous recombination.
PALB2Partner and localizer of BRCA2Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
FLCNFolliculinMulti-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.
MUTYHAdenine DNA glycosylaseInvolved in oxidative DNA damage repair.
NF1NeurofibrominStimulates the GTPase activity of Ras.
RAD52DNA repair protein RAD52 homologInvolved in double-stranded break repair.
RAD54LDNA repair and recombination protein RAD54-likeMultifunctional ATPase that plays a role in homologous recombination (HR) which is a major pathway for repairing DNA double-strand breaks (DSBs), single-stranded DNA (ssDNA) gaps, and stalled or collapsed replication forks.
RETProto-oncogene tyrosine-protein kinase receptor RetReceptor 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: 2 · Unknown: 6 · Druggable fraction: 0.38

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.

FamilyGenesFoldFDR
Kinase36.4×0.051
Enzyme (other)21.8×0.741
Scaffold/PPI11.3×0.837
Other/Unknown60.8×0.837
Transcription factor10.6×0.837

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
KRASEnzyme (other)yes3.6.5.2Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
BRAFKinaseyes2.7.10.2Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
FGFR1Kinaseyes2.7.10.1Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
SDHAOther/UnknownnoFRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
BRCA1Transcription factorno2.3.2.27BRCT_dom, Znf_RING, BRCA1
BRCA2Other/UnknownnoBRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
PALB2Scaffold/PPInoWD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
FLCNOther/UnknownnoFolliculin, Folliculin_DENN, Folliculin/SMCR8_longin
MUTYHOther/UnknownnoNUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain
NF1Other/UnknownnoCRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
RAD52Other/UnknownnoDNA_recomb/repair_Rad52, Rad52_Rad59_Rad22, Rad52_fam
RAD54LEnzyme (other)yes3.6.4.B9SNF2_N, Helicase_C-like, Helicase_ATP-bd
RETKinaseyes2.7.10.1Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)13
unknown0

Top tissues across cohort

TissueCohort genes
buccal mucosa cell4
calcaneal tendon3
ventricular zone3
colonic epithelium2
male germ line stem cell (sensu Vertebrata) in testis2
secondary oocyte2
cerebellar hemisphere2
right hemisphere of cerebellum2
nipple1
pylorus1
trigeminal ganglion1
stromal cell of endometrium1
apex of heart1
heart left ventricle1
mucosa of transverse colon1
primordial germ cell in gonad1
oocyte1
cerebellar cortex1
adrenal tissue1
right lobe of thyroid gland1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
KRAS298ubiquitousmarkertrigeminal ganglion, pylorus, nipple
BRAF265ubiquitousmarkerbuccal mucosa cell, colonic epithelium, calcaneal tendon
FGFR1292ubiquitousmarkerbuccal mucosa cell, stromal cell of endometrium, calcaneal tendon
SDHA143ubiquitousmarkerapex of heart, heart left ventricle, mucosa of transverse colon
BRCA1208ubiquitousmarkerventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
BRCA2184ubiquitousmarkermale germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
PALB2232ubiquitousyessecondary oocyte, buccal mucosa cell, oocyte
FLCN261ubiquitousmarkerbuccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere
MUTYH134ubiquitousmarkercerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
NF1283ubiquitousmarkercolonic epithelium, calcaneal tendon, adrenal tissue
RAD52218ubiquitousmarkerright uterine tube, sural nerve, right lobe of thyroid gland
RAD54L173ubiquitousyesleft testis, right testis, ventricular zone
RET193broadmarkersubstantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

SymbolInteractor count
KRAS14,509
BRCA19,064
BRAF7,394
SDHA6,141
FGFR15,693
PALB25,641
NF15,540
BRCA24,839
RET4,203
RAD54L2,927

Intra-cohort edges

ABSources
BRAFBRCA2biogrid_interaction
BRAFKRASbiogrid_interaction, intact, string_interaction
BRAFNF1string_interaction
BRCA1BRCA2string_interaction
BRCA1NF1string_interaction
BRCA1PALB2biogrid_interaction, intact, string_interaction
BRCA1RAD52string_interaction
BRCA1RAD54Lstring_interaction
BRCA2PALB2biogrid_interaction, intact, string_interaction
BRCA2RAD52string_interaction
BRCA2RAD54Lstring_interaction
KRASNF1string_interaction
NF1RETstring_interaction
PALB2RAD54Lstring_interaction
RAD52RAD54Lstring_interaction

Structural data

PDB: 13 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
KRASP01116511
BRAFP15056131
FGFR1P1136283
RETP0794934
BRCA1P3839833
NF1P2135926
BRCA2P5158714
RAD52P4335111
SDHAP310405
PALB2Q86YC24
FLCNQ8NFG44
MUTYHQ9UIF73
RAD54LQ926981

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 192. Enrichment computed across 13 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Impaired BRCA2 binding to PALB23114.2×1e-04BRCA1, BRCA2, PALB2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function3105.7×1e-04BRCA1, BRCA2, PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function3105.7×1e-04BRCA1, BRCA2, PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function3105.7×1e-04BRCA1, BRCA2, PALB2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)398.5×1e-04BRCA1, BRCA2, PALB2
Homologous DNA Pairing and Strand Exchange395.2×1e-04BRCA1, BRCA2, PALB2
RAF/MAP kinase cascade525.4×1e-04KRAS, BRAF, FGFR1, NF1, RET
Resolution of D-loop Structures through Holliday Junction Intermediates375.1×2e-04BRCA1, BRCA2, PALB2
RAS signaling downstream of NF1 loss-of-function variants2271.9×5e-04KRAS, NF1
HDR through Homologous Recombination (HRR)347.6×6e-04BRCA1, BRCA2, PALB2
Defective homologous recombination repair (HRR) due to PALB2 loss of function2158.6×0.001BRCA1, BRCA2
HDR through MMEJ (alt-NHEJ)2146.4×0.001BRCA2, RAD52
Diseases of DNA Double-Strand Break Repair2135.9×0.001BRCA1, BRCA2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function2135.9×0.001BRCA1, BRCA2
Resolution of D-Loop Structures2105.7×0.002BRCA1, BRCA2
Diseases of DNA repair295.2×0.002BRCA1, BRCA2
SHC-mediated cascade:FGFR1282.8×0.003KRAS, FGFR1
FRS-mediated FGFR1 signaling276.1×0.003KRAS, FGFR1
Negative regulation of FGFR1 signaling261.4×0.005BRAF, FGFR1
Defective MUTYH substrate binding1951.7×0.005MUTYH
Defective MUTYH substrate processing1951.7×0.005MUTYH
RAF activation256.0×0.005KRAS, BRAF
Signaling by high-kinase activity BRAF mutants252.9×0.005KRAS, BRAF
Homology Directed Repair251.4×0.005BRCA1, BRCA2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)251.4×0.005BRCA1, BRCA2
Impaired BRCA2 binding to RAD51251.4×0.005BRCA1, BRCA2
Signaling by FGFR1 in disease248.8×0.005KRAS, FGFR1
HDR through Single Strand Annealing (SSA)248.8×0.005BRCA1, RAD52
Meiosis247.6×0.005BRCA1, BRCA2
MAP2K and MAPK activation247.6×0.005KRAS, BRAF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
double-strand break repair via homologous recombination560.0×2e-06BRCA1, BRCA2, PALB2, RAD52, RAD54L
MAPK cascade558.9×2e-06KRAS, BRAF, FGFR1, NF1, RET
forebrain astrocyte development2864.2×2e-04KRAS, NF1
chordate embryonic development2432.1×7e-04BRCA1, FGFR1
visual learning370.7×7e-04KRAS, BRAF, NF1
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand2235.7×0.002NF1, RET
double-strand break repair346.9×0.002BRCA1, BRCA2, RAD52
regulation of DNA damage checkpoint2172.8×0.002BRCA1, BRCA2
regulation of synaptic transmission, GABAergic2162.0×0.002KRAS, NF1
inner cell mass cell proliferation2152.5×0.002BRCA2, PALB2
regulation of long-term neuronal synaptic plasticity2152.5×0.002KRAS, NF1
cardiac muscle cell proliferation289.4×0.007KRAS, FGFR1
Rac protein signal transduction286.4×0.007KRAS, NF1
positive regulation of gene expression411.9×0.007KRAS, BRAF, BRCA1, RET
ureteric bud development270.1×0.009FGFR1, RET
response to ionizing radiation263.2×0.009BRCA1, RAD54L
cellular response to ionizing radiation263.2×0.009BRCA1, BRCA2
positive regulation of mast cell apoptotic process11296.3×0.011NF1
double-strand break repair via single-strand annealing11296.3×0.011RAD52
regulation of glial cell differentiation11296.3×0.011NF1
response to mineralocorticoid11296.3×0.011KRAS
observational learning11296.3×0.011NF1
negative regulation of cell proliferation involved in kidney development11296.3×0.011FLCN
DNA recombination251.9×0.011RAD52, RAD54L
ERK1 and ERK2 cascade248.9×0.011BRAF, FLCN
stem cell proliferation248.0×0.011FGFR1, NF1
long-term synaptic potentiation243.2×0.012BRAF, NF1
DNA repair314.7×0.012BRCA1, MUTYH, RAD54L
embryonic epithelial tube formation1648.1×0.015RET
posterior midgut development1648.1×0.015RET

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 8 · Undrugged: 5

Druggability breadth: 9 of 13 evidence-associated genes (69%) 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.

SymbolExample approved molecule
KRASVEMURAFENIB
BRAFVEMURAFENIB
FGFR1PONATINIB
SDHALINEZOLID
BRCA1RIBOFLAVIN
RAD52FENOLDOPAM MESYLATE
RETPONATINIB

Top cohort targets by molecule count

SymbolMoleculesMax phase
RET1354
FGFR1934
BRAF484
RAD52244
BRCA1124
KRAS114
SDHA14
RAD54L12
BRCA200
PALB200

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
VEMURAFENIB4BRAF, KRAS, RET
DABRAFENIB4BRAF, KRAS
LONAFARNIB4KRAS
SOTORASIB4KRAS
ADAGRASIB4KRAS
PONATINIB4BRAF, FGFR1, RET
FEDRATINIB4BRAF, FGFR1, RET
SORAFENIB4BRAF, FGFR1, RET
DASATINIB ANHYDROUS4BRAF, RET
RUXOLITINIB4BRAF, RET
INFIGRATINIB PHOSPHATE4BRAF, FGFR1, RET
INFIGRATINIB4BRAF, FGFR1, RET
REGORAFENIB4BRAF, FGFR1, RET
COBIMETINIB4BRAF
NILOTINIB4BRAF, RET
ABEMACICLIB4BRAF
ENCORAFENIB4BRAF
TOVORAFENIB4BRAF
PAZOPANIB4BRAF, FGFR1, RET
DASATINIB4BRAF, FGFR1, RET
ERLOTINIB4BRAF, RET
GEFITINIB4BRAF, RET
IMATINIB4BRAF
PEMIGATINIB4FGFR1
NINTEDANIB4FGFR1, RET
TIVOZANIB4FGFR1, RET
LENVATINIB4FGFR1, RET
AXITINIB4FGFR1, RET
NICLOSAMIDE4FGFR1
ENTRECTINIB4FGFR1, RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

SymbolAssaysType breakdown
RET1,586Binding:1573, Functional:10, ADMET:3
FGFR11,465Binding:1428, Functional:24, ADMET:13
BRAF1,442Binding:1400, Functional:37, ADMET:5
KRAS861Binding:829, Functional:32
RAD5244Binding:40, Functional:3, ADMET:1
BRCA113Binding:9, Functional:4
SDHA3Binding:3
RAD54L3Functional:2, Binding:1
MUTYH1Functional:1

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
KRAS3.6.5.2small monomeric GTPase
BRAF2.7.10.2, 2.7.11.1non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
FGFR12.7.10.1receptor protein-tyrosine kinase
BRCA12.3.2.27RING-type E3 ubiquitin transferase
RAD54L3.6.4.B9
RET2.7.10.1receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
KRAS861
BRAF1,442
FGFR11,465
RET1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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.

CompoundMax phaseCohort target (bioactivity)
VEMURAFENIB4BRAF, KRAS, RET
LONAFARNIB4KRAS
SOTORASIB4KRAS
ADAGRASIB4KRAS
PONATINIB4BRAF, FGFR1, RET
FEDRATINIB4BRAF, FGFR1, RET
SORAFENIB4BRAF, FGFR1, RET
DASATINIB ANHYDROUS4BRAF, RET
RUXOLITINIB4BRAF, RET
INFIGRATINIB PHOSPHATE4BRAF, FGFR1, RET
INFIGRATINIB4BRAF, FGFR1, RET
REGORAFENIB4BRAF, FGFR1, RET
COBIMETINIB4BRAF
NILOTINIB4BRAF, RET
ABEMACICLIB4BRAF
ENCORAFENIB4BRAF
PAZOPANIB4BRAF, FGFR1, RET
DASATINIB4BRAF, FGFR1, RET
ERLOTINIB4BRAF, RET
GEFITINIB4BRAF, RET
IMATINIB4BRAF
PEMIGATINIB4FGFR1
NINTEDANIB4FGFR1, RET
TIVOZANIB4FGFR1, RET
LENVATINIB4FGFR1, RET
AXITINIB4FGFR1, RET
NICLOSAMIDE4FGFR1
ENTRECTINIB4FGFR1, RET

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)7KRAS, BRAF, FGFR1, SDHA, BRCA1, RAD52, RET
BPhased (≥1) drug, not yet approved1RAD54L
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug5BRCA2, PALB2, FLCN, MUTYH, NF1

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
BRCA20BRCA1
PALB20BRCA1
NF10KRAS, BRAF
FLCN0—
MUTYH1—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

PhaseTrials
PHASE23
Not specified3
PHASE12
PHASE41
PHASE1/PHASE21

Top trials by phase / activity

NCTPhaseStatusTitle
NCT03975829PHASE4RECRUITINGPediatric Long-Term Follow-up and Rollover Study
NCT01837862PHASE1/PHASE2COMPLETEDA Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas
NCT02372409PHASE2TERMINATEDUsing MRI-Guided Laser Heat Ablation to Induce Disruption of the Peritumoral Blood Brain Barrier to Enhance Delivery and Efficacy of Treatment of Pediatric Brain Tumors
NCT02684058PHASE2COMPLETEDStudy 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
NCT04985604PHASE2TERMINATEDTovorafenib (DAY101) Monotherapy for Patients With Melanoma and Other Solid Tumors
NCT04541082PHASE1RECRUITINGPhase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms
NCT07121829PHASE1TERMINATEDTovorafenib (DAY101) or in Combination With Pimasertib for Participants With Melanoma and Other Solid Tumors
NCT04065776Not specifiedRECRUITINGEvaluation of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma
NCT06915649Not specifiedRECRUITINGExploration and Evaluation of Amygdalo-Hippocampectomy According to Prof. Coubes’ Technique: An Anatomical, Clinical, and Educational Approach
NCT05934630Not specifiedTERMINATEDTesting Cerebrospinal Fluid for Cell-free Tumor DNA in Children, Adolescents, and Young Adults With Brain Tumors

Drugs tested across these trials (top 30)

MoleculeMax phaseTrials referencing
DABRAFENIB42
TOVORAFENIB42
TRAMETINIB42
MEBENDAZOLE41
ONC-20611
CHEMBL543395002

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 8 predictive associations from 8 curated evidence items; also 8 diagnostic, 2 oncogenic.

Molecular subtypeTherapyEffectLevelCIViC
BRAF V600EDabrafenib + TrametinibSensitivity/ResponseCIViC AEID11313
BRAF V600E OR KIAA1549::BRAF FusionSelumetinibSensitivity/ResponseCIViC BEID11316
BRAF V600EVemurafenibSensitivity/ResponseCIViC CEID3772
FGFR1 N546KPemigatinibSensitivity/ResponseCIViC CEID10325
GOPC::ROS1 FusionEntrectinibSensitivity/ResponseCIViC CEID12604
NF1 Mutation AND Methylation signature PA-NF1TrametinibSensitivity/ResponseCIViC CEID12269
NF1 Splice Site (c.205-1G>C) AND NF1 G629RVincristine + Carboplatin + Trametinib + SelumetinibSensitivity/ResponseCIViC CEID12271
BRAF T599dupCIViC CEID2990

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
v2.0.2

Sources 72

This page pulls from 72 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondbsnpdepmapdiamond_similaritydoidefoensemblentrezesm2_similarityfantom5_genefantom5_promotergardgenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncintactinterpromedgenmeshmimmondomondochildmondoparentncitorphanetpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralsctidscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptufeatureumlsuniprot