Hilar cholangiocarcinoma

Summary

Hilar cholangiocarcinoma (MONDO:0003345) is a disease with 1 cohort gene and 60 clinical trials. Top therapeutic interventions include cisplatin, binimetinib, and sacituzumab govitecan.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 10
• Clinical trials: 60

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated
Annual incidence	1-9 / 100 000	1.5	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0012334	Extrahepatic cholestasis	Very frequent (80-99%)
HP:0030153	Cholangiocarcinoma	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hilar cholangiocarcinoma
Mondo ID	MONDO:0003345
EFO	EFO:1001959
MeSH	D018285
Orphanet	99978
DOID	DOID:4927, DOID:5246
ICD-11	1571104786
NCIT	C36077
SNOMED CT	253017000
UMLS	C4045991
MedGen	878855
GARD	0010175
Anatomy (UBERON)	UBERON:0015423
Is cancer (heuristic)	no

Also known as: cholangiocarcinoma of hilar portion of hepatic duct · hilar CC · hilar CCA · hilar cholangiocarcinoma · hilar portion of hepatic duct cholangiocarcinoma · Klatskin tumor · Klatskin’s tumor · perihilar cholangiocarcinoma

Data availability: 1 ClinVar variant · 13 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › digestive system cancer › liver cancer › biliary tract cancer › bile duct cancer › intrahepatic bile duct cancer › intrahepatic cholangiocarcinoma › hilar cholangiocarcinoma

Related subtypes (5): mucinous intrahepatic cholangiocarcinoma, cholangiolocellular carcinoma, signet ring cell intrahepatic cholangiocarcinoma, sarcomatous intrahepatic cholangiocarcinoma, perihilar intrahepatic cholangiocarcinoma

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
559953	NM_000038.6(APC):c.4658C>T (p.Ala1553Val)	APC	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APC	Orphanet:220460	Attenuated familial adenomatous polyposis
APC	Orphanet:261584	5q22 microdeletion syndrome
APC	Orphanet:314022	Gastric adenocarcinoma and proximal polyposis of the stomach
APC	Orphanet:3258	Cenani-Lenz syndrome
APC	Orphanet:873	Desmoid tumor

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APC	Adenomatous polyposis coli protein	Tumor suppressor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
medial globus pallidus	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APC	297	ubiquitous	marker	substantia nigra pars compacta, substantia nigra pars reticulata, medial globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APC	2,903

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APC	P25054	31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
APC truncation mutants are not K63 polyubiquitinated	1	11420.0×	0.003	APC
Signaling by AXIN mutants	1	1038.2×	0.003	APC
Signaling by CTNNB1 phospho-site mutants	1	1038.2×	0.003	APC
Signaling by APC mutants	1	1038.2×	0.003	APC
Signaling by AMER1 mutants	1	1038.2×	0.003	APC
APC truncation mutants have impaired AXIN binding	1	815.7×	0.003	APC
AXIN missense mutants destabilize the destruction complex	1	815.7×	0.003	APC
Truncations of AMER1 destabilize the destruction complex	1	815.7×	0.003	APC
Signaling by GSK3beta mutants	1	761.3×	0.003	APC
CTNNB1 S33 mutants aren’t phosphorylated	1	761.3×	0.003	APC
CTNNB1 S37 mutants aren’t phosphorylated	1	761.3×	0.003	APC
CTNNB1 S45 mutants aren’t phosphorylated	1	761.3×	0.003	APC
CTNNB1 T41 mutants aren’t phosphorylated	1	761.3×	0.003	APC
Beta-catenin phosphorylation cascade	1	671.8×	0.003	APC
Signaling by WNT in cancer	1	601.0×	0.003	APC
Apoptotic cleavage of cellular proteins	1	475.8×	0.004	APC
Apoptotic execution phase	1	475.8×	0.004	APC
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	356.9×	0.005	APC
Ovarian tumor domain proteases	1	278.5×	0.006	APC
Deactivation of the beta-catenin transactivating complex	1	233.1×	0.007	APC
Degradation of beta-catenin by the destruction complex	1	173.0×	0.008	APC
Apoptosis	1	167.9×	0.008	APC
Programmed Cell Death	1	146.4×	0.009	APC
Deubiquitination	1	124.1×	0.010	APC
TCF dependent signaling in response to WNT	1	117.7×	0.011	APC
Signaling by WNT	1	112.0×	0.011	APC
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.020	APC
Post-translational protein modification	1	19.2×	0.058	APC
Disease	1	13.1×	0.082	APC
Metabolism of proteins	1	12.4×	0.084	APC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of microtubule-based movement	1	2808.7×	0.003	APC
negative regulation of cell cycle G1/S phase transition	1	2407.4×	0.003	APC
positive regulation of protein localization to centrosome	1	2407.4×	0.003	APC
negative regulation of cyclin-dependent protein serine/threonine kinase activity	1	2106.5×	0.003	APC
regulation of microtubule-based process	1	1872.4×	0.003	APC
regulation of attachment of spindle microtubules to kinetochore	1	1685.2×	0.003	APC
heart valve development	1	1532.0×	0.003	APC
positive regulation of pseudopodium assembly	1	1296.3×	0.003	APC
endocardial cushion morphogenesis	1	842.6×	0.004	APC
mitotic spindle assembly checkpoint signaling	1	561.7×	0.005	APC
cell fate specification	1	526.6×	0.005	APC
negative regulation of microtubule depolymerization	1	495.6×	0.005	APC
pattern specification process	1	468.1×	0.005	APC
negative regulation of G1/S transition of mitotic cell cycle	1	358.6×	0.006	APC
bicellular tight junction assembly	1	330.4×	0.006	APC
mitotic cytokinesis	1	259.3×	0.007	APC
insulin receptor signaling pathway	1	221.7×	0.008	APC
positive regulation of protein catabolic process	1	203.0×	0.008	APC
positive regulation of cold-induced thermogenesis	1	163.6×	0.010	APC
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.013	APC
protein-containing complex assembly	1	113.9×	0.013	APC
Wnt signaling pathway	1	99.7×	0.014	APC
positive regulation of cell migration	1	61.7×	0.020	APC
cell migration	1	61.5×	0.020	APC
positive regulation of apoptotic process	1	56.7×	0.021	APC
DNA damage response	1	53.5×	0.021	APC
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.021	APC
nervous system development	1	45.9×	0.023	APC
negative regulation of cell population proliferation	1	42.1×	0.025	APC
cell adhesion	1	37.5×	0.027	APC

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Porfimer Sodium	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Binimetinib, Fluorouracil, Oxaliplatin, Sacituzumab Govitecan.

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APC	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
APC	24	Binding:24

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	APC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APC	24	—

Clinical trials & evidence

Clinical trials

Clinical trials: 60.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	35
PHASE2	13
PHASE1	4
PHASE4	3
PHASE2/PHASE3	2
PHASE1/PHASE2	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05551299	PHASE4	RECRUITING	Treatment of Non-resectable Bile Duct Cancer with Radiofrequency Ablation or Photodynamic Therapy
NCT00721175	PHASE4	COMPLETED	Efficacy and Cost Analysis of Plastic Stent Compare to Metallic Stent in Hilar Cholangiocarcinoma
NCT01125865	PHASE4	UNKNOWN	Uncovered Self-expandable Metal Stent Versus Double Layer Plastic Stent for Malignant Hilar Stricture
NCT06923475	PHASE2/PHASE3	NOT_YET_RECRUITING	Neoadjuvant Gemcitabine and Cisplatin in Combination With Perioperative Pembrolizumab Versus Upfront Surgery for Patients With Primary Resectable and Borderline Resectable Perihilar and Distal Cholangiocarcinoma
NCT02082522	PHASE3	TERMINATED	Efficacy and Safety Study of PDT Using Photofrin in Unresectable Advanced Perihilar Cholangiocarcinoma (OPUS)
NCT02108145	PHASE2/PHASE3	UNKNOWN	Percutaneous Bilateral Versus Unilateral Metal Stent for Hilar Cholangiocarcinoma
NCT05430698	PHASE2	RECRUITING	PD-1 Antibody Plus GEMOX as Postoperative Adjuvant Therapy in Perihilar Cholangiocarcinoma
NCT05564403	PHASE2	ACTIVE_NOT_RECRUITING	Study of Chemotherapy, With or Without Binimetinib in Advanced Biliary Tract Cancers in 2nd Line Setting (A ComboMATCH Treatment Trial)
NCT06178588	PHASE2	ACTIVE_NOT_RECRUITING	Sacituzumab Govitecan for the Treatment for Patients With Locally Advanced, Recurrent, or Metastatic Cholangiocarcinoma
NCT06717464	PHASE2	ACTIVE_NOT_RECRUITING	Toripalimab Combined With Capecitabine as Postoperative Adjuvant Therapy for Patients With Resectable Advanced Extrahepatic Biliary Tract Cancer
NCT07030140	PHASE2	RECRUITING	Phase II Study of Neoadjuvant Tislelizumab Plus Radiotherapy and GP Chemotherapy for Borderline/Unresectable Hilar Cholangiocarcinoma
NCT07471165	PHASE2	NOT_YET_RECRUITING	A Prospective, Single-Arm, Phase II Study: PD-L1 Monoclonal Antibody + Chemoradiotherapy as Bridge Therapy to Liver Transplantation for Locally Advanced Perihilar Cholangiocarcinoma (ACHIEVE-LT)
NCT01093222	PHASE2	COMPLETED	Sorafenib Tosylate and Erlotinib Hydrochloride in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gallbladder Cancer or Cholangiocarcinoma
NCT02042443	PHASE2	COMPLETED	Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery
NCT02178280	PHASE1/PHASE2	UNKNOWN	Safety Study of Liver Transplantation for Hilar Cholangiocarcinoma
NCT02955771	PHASE2	TERMINATED	Efficacy and Safety Study of PDT Using Deuteporfin for Unresectable Advanced Perihilar Cholangiocarcinoma
NCT03003065	PHASE2	COMPLETED	Safety and Tumoricidal Effect of Low Dose Foscan PDT in Patients With Inoperable Bile Duct Cancers
NCT03620292	PHASE1/PHASE2	UNKNOWN	Fluorescence Image Guided Surgery in Cholangiocarcinoma
NCT05024513	PHASE2	COMPLETED	Biliary Drainage Plus HAIC in Locally Advanced pCCA
NCT05239169	PHASE2	COMPLETED	Immunotherapy With Durva and Treme With or Without Capecitabine in Adjuvant Treatment for Biliary Tract Cancer
NCT06739252	PHASE2	TERMINATED	Perioperative Treatment of High-risk Resectable CCA With HAIC Plus A+T: Neobrave CCA
NCT00630890	PHASE1	TERMINATED	Cyberknife Radiosurgery Boost for Hilar Cholangiocarcinoma (Klatskin Tumor)
NCT01825603	PHASE1	COMPLETED	ADH-1, Gemcitabine Hydrochloride & Cisplatin in Treating Metastatic Pancreatic or Biliary Tract Cancer
NCT02856568	PHASE1	WITHDRAWN	Ricolinostat, Gemcitabine Hydrochloride, and Cisplatin in Treating Patients With Unresectable or Metastatic Cholangiocarcinoma
NCT06420349	PHASE1	TERMINATED	NXP800 for the Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma
NCT04993131	Not specified	RECRUITING	Liver Transplantation for Non-resectable Perihilar Cholangiocarcinoma
NCT05546372	Not specified	RECRUITING	Endobiliary Radiofrequency Ablation for Malignant Biliary Obstruction Due to Perihilar Cholangiocarcinoma
NCT06125769	Not specified	RECRUITING	LIver TrAnspLantation for Non-resectable Peri-HIlar cholangioCArcinoma (LITALHICA)
NCT06175845	Not specified	NOT_YET_RECRUITING	Endoscopic Radiofrequency Ablation for Unresectable Cholangiocarcinoma
NCT06493734	Not specified	RECRUITING	Stereotactic Body Radiation Therapy After Chemotherapy for Unresectable Perihilar Cholangiocarcinoma
NCT06720883	Not specified	RECRUITING	Robotically Assisted Surgery For Perihilar Cholangiocarcinoma: A Prospective Study
NCT06964425	Not specified	RECRUITING	Raman Spectroscopy in the Diagnosis of Extrahepatic Cholangiocarcinoma - a Pilot Study
NCT06986486	Not specified	RECRUITING	Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma
NCT07161869	Not specified	NOT_YET_RECRUITING	Preoperative Evaluation of Lymph Nodes of Cholangiocarcinoma (POELH-III)
NCT07176962	Not specified	RECRUITING	A Cell-free DNA Methylation Blood-Based Test for Biliary Tract Cancers Screening
NCT01549795	Not specified	UNKNOWN	Liver Transplantation for Hilar Cholangiocarcinoma in Association With Neoadjuvant Radio- and Chemo-therapy
NCT01715402	Not specified	UNKNOWN	Optimization of Health Expenditure in Liver Surgery
NCT02166970	Not specified	COMPLETED	Single Versus Multiple Deployment of Metallic Stents for Inoperable Malignant Hilar Biliary Obstruction
NCT02504957	Not specified	COMPLETED	Photodynamic Therapy With Polyhematoporphyrin for Malignant Biliary Obstruction
NCT02801500	Not specified	UNKNOWN	Superior Bilioenteric Anastomosis by Magnetic Compressive Technique

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CISPLATIN	4	3
BINIMETINIB	4	1
SACITUZUMAB GOVITECAN	4	1
SORAFENIB	4	1
TEMOPORFIN	4	1
TRAMETINIB	4	1
RICOLINOSTAT	2	1
ADH-1	1	1
CHEMBL5433950	0	1