Fibrolamellar Hepatocellular Carcinoma

MONDO:0006210 Pathograph 28 Show in embeddings browser hepatocellular carcinoma

Fibrolamellar carcinoma is a rare primary liver cancer of adolescents and young adults that arises in an otherwise normal, non-cirrhotic liver and without the viral, alcoholic or metabolic risk factors that define conventional hepatocellular carcinoma. Nearly every tumour carries the same single lesion: a somatic ~400 kb deletion on chromosome 19 that fuses exon 1 of DNAJB1 to the catalytic domain of PRKACA, producing a chimeric protein kinase A catalytic subunit. That chimera is not merely more PKA - it is overexpressed relative to wild-type, it acquires an Hsp70-recruiting scaffolding function the normal kinase lacks, and overexpressing wild-type PRKACA does not reproduce its oncogenic effect. Engineering the equivalent fusion into mouse liver, with no other genetic change and no carcinogen, produces tumours resembling the human disease. Whole-genome sequencing finds no recurrent second hit, which leaves this among the closest things in solid oncology to a one-lesion cancer. Histologically the tumour is built of large eosinophilic, mitochondria-rich polygonal cells separated by the parallel lamellar collagen bands that give the disease its name. Surgical resection is the only intervention with a demonstrated survival effect; chemotherapy and radiation have none.

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15
Pathophys.
2
Histopath.
10
Phenotypes
2
Gaps
28
Pathograph
1
Genes
6
Medical Actions
3
Differentials
4
Trials
5
Models
1
Deep Research
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Classifications

ICD-O Morphology
Carcinoma
Harrison's Part
ONCOLOGY HEMATOLOGY
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Discussions and Knowledge Gaps

2
How does a hepatocyte carrying the DNAJB1-PRKACA fusion induce the parallel lamellar collagen bands the disease is named for?
KNOWLEDGE GAP flc_lamellar_stroma_mechanism
Attached to
pathophysiology#Hepatocyte Transformation and Clonal Proliferation pathophysiology#Lamellar Fibrous Stroma Formation
The lamellar stroma is the tumour's defining histologic feature and the origin of its name, yet the entry cannot connect it to the driver. TGF-beta overexpression is the proposed route in the literature, but the support is correlative and histological rather than a demonstrated causal chain, so the edge from transformation to stroma is curated with unknown intermediates and no evidence attached. The gap matters because the fibrosis is not cirrhotic and the surrounding liver is normal, so whatever drives it is tumour-directed rather than a background process.
Is fibrolamellar carcinoma a subtype of hepatocellular carcinoma or a separate entity, and what should the entry assert?
INTERPRETATION flc_who5_versus_mondo_placement
Attached to
disease#Fibrolamellar Hepatocellular Carcinoma differential_diagnoses#Conventional Hepatocellular Carcinoma
MONDO places MONDO:0006210 under hepatocellular carcinoma, and this entry's `parents` follows it. The evidence curated here points the other way: the genomic landscape is distinct, the driver is absent from conventional hepatocellular carcinoma and from every other liver tumour tested, the patient population and risk-factor profile do not overlap, and the published sequencing describes it as "a distinct carcinoma". The entry does not attempt to resolve the ontology question - it uses MONDO's term and hierarchy as given, curates the evidence that bears on the placement, and records the disagreement here rather than silently asserting either answer.
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Pathophysiology

15
Chromosome 19 Deletion Creating the DNAJB1-PRKACA Fusion
A somatic heterozygous deletion of roughly 400 kb on chromosome 19 joins DNAJB1 in frame to PRKACA. The deletion is present in essentially every fibrolamellar carcinoma and in no adjacent normal liver, and whole-genome sequencing finds no recurrent second structural event alongside it.
DNAJB1 hgnc:5270 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJB1 (hgnc:5270). hgnc:5270 is a gene from the HUGO Gene Nomenclature Committee. PRKACA hgnc:9380 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRKACA (hgnc:9380). hgnc:9380 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Chimeric DNAJ-PKAc Kinase Expression The fusion transcript is translated into a chimeric protein that is detectable in tumour tissue and retains kinase activity.
Show evidence (3 references)
PMID:24578576 SUPPORT Human Clinical
"We identified a chimeric transcript that is expressed in FL-HCC but not in adjacent normal liver and that arises as the result of a ~400-kilobase deletion on chromosome 19."
The founding observation defining this node - the deletion, its size, and its tumour restriction.
PMID:24578576 SUPPORT Human Clinical
"Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis."
Quantifies the near-universal recurrence on which this entry's single-driver framing rests.
PMID:25605237 SUPPORT Human Clinical
"There are relatively few coding, somatic mutations in this cancer, putting it on the low end of the mutational spectrum."
Whole-genome evidence for the low mutational burden that makes this lesion interpretable as the driver rather than one of many.
Chimeric DNAJ-PKAc Kinase Expression
The chimera carries the DNAJB1 amino-terminal chaperone-binding domain fused to the PRKACA catalytic domain. Its transcript is expressed about tenfold above wild-type PRKACA, so the tumour cell holds far more of the mutant kinase than of the normal one.
cAMP-dependent protein kinase activity GO:0004691 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased cAMP-dependent protein kinase activity (GO:0004691). GO:0004691 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Elevated cAMP-Stimulated PKA Activity
Acquired Hsp70 Scaffolding Function
Show evidence (2 references)
PMID:24578576 SUPPORT Human Clinical
"The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A."
Describes the domain architecture of the chimera this node names.
PMID:27027723 SUPPORT Human Clinical
"DNAJB1-PRKACA was expressed 10-fold higher than the wild-type PRKACA transcript, resulting in overexpression of the mutant protein in tumors."
Quantifies the expression imbalance between mutant and wild-type kinase.
Elevated cAMP-Stimulated PKA Activity
Tumours show higher cAMP-stimulated PKA catalytic activity than normal liver. The mutant and wild-type kinases have similar Km values, so the excess activity is a consequence of how much mutant kinase is present rather than of a changed affinity for substrate.
Downstream
AURKA-GSK3 Sub-Network Activation
SIK Inactivation
Show evidence (1 reference)
PMID:27027723 SUPPORT Human Clinical
"Consequently, FL-HCCs possess elevated cAMP-stimulated PKA activity compared to normal livers, despite similar Kms between the mutant and wild-type kinases."
States both the elevated activity and the Km comparison that locates the cause in abundance rather than in altered catalysis.
Acquired Hsp70 Scaffolding Function
The retained DNAJ domain lets the fusion recruit Hsp70, a property wild-type PKA does not have. A-kinase anchoring protein Lbc, itself upregulated in these tumours, clusters the resulting DNAJ-PKAc/Hsp70 subcomplexes with a RAF-MEK-ERK module, so the fusion does not simply signal harder - it assembles a signalling complex the normal kinase never forms. This is the clearest evidence that the lesion is neomorphic rather than merely activating.
Experimental models
AML12 DNAJ-PKAc gene-edited hepatocyte line CELL LINE The line reproduces the fusion's Hsp70 recruitment and ERK-biased signalling, and its proliferation is selectively blocked by Hsp70 plus MEK inhibitor combinations.
Downstream
ERK-Biased MAPK Signalling Clustering the fusion with a RAF-MEK-ERK module is what redirects the cell's signalling output toward ERK.
Show evidence (2 references)
PMID:31063128 SUPPORT In Vitro
"a unique property of this fusion enzyme is the ability to recruit heat shock protein 70 (Hsp70)"
Establishes the acquired, wild-type-absent property this node describes.
PMID:33370777 SUPPORT In Vitro
"The J-domain also alters several biochemical properties of the RIIβ holoenzyme: It is easier to activate with cAMP, and the cooperativity is reduced."
A measured consequence of the retained J-domain, independent of the Hsp70 result: the same domain that recruits Hsp70 also changes how the holoenzyme responds to cAMP. Graded IN_VITRO - the paper is a cryo-EM and small-angle-scattering study of purified holoenzyme, with molecular dynamics as one component rather than the whole method.
ERK-Biased MAPK Signalling
Phosphoproteomic profiling shows the fusion shifts the cell's signalling landscape toward ERK activation and engages downstream kinase cascades.
MAPK cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hepatocyte Transformation and Clonal Proliferation
Show evidence (1 reference)
PMID:31063128 SUPPORT In Vitro
"Phosphoproteomic profiling demonstrates that DNAJ-PKAc biases the signaling landscape toward ERK activation and engages downstream kinase cascades."
Direct phosphoproteomic evidence for the ERK bias this node asserts.
SIK Inactivation
The fusion kinase inactivates the salt-inducible kinases, which act as tumour suppressors in this setting. This is the phosphorylation event itself, separate from the transcriptional consequence it releases.
Downstream
CRTC2-p300 Transcriptional Reprogramming Losing SIK activity is what releases the CRTC2-p300 coactivator complex; the source states the two steps in that order.
Show evidence (1 reference)
PMID:39326063 SUPPORT In Vitro
"DNAJB1-PRKACA inactivates the SIK tumor suppressors in patient-derived FLC cells and engineered models."
The inactivation event this node records, shown in both patient-derived cells and engineered models.
CRTC2-p300 Transcriptional Reprogramming
With SIK activity lost, the CRTC2 coactivator and the p300 acetyltransferase drive a transcriptional program that supports tumour growth. This arm was defined in 2024 by combining model systems with human tumour specimens.
positive regulation of transcription by RNA polymerase II GO:0045944 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hepatocyte Transformation and Clonal Proliferation
Show evidence (1 reference)
PMID:39326063 SUPPORT In Vitro
"DNAJB1-PRKACA-mediated inactivation of the SIK stimulates CRTC2-p300-mediated transcription to drive tumor growth."
Names the coactivator complex and connects it to growth, which is the claim this node carries.
AURKA-GSK3 Sub-Network Activation
Phosphoproteomics across PKA-activating lesions identifies an Aurora kinase A / GSK3 sub-network as one of two conserved signalling outputs downstream of the fusion. Aurora kinase A is also raised in human tumours by transcriptomics, and it is the target that took the first fusion-rationalised drug into a trial in this disease.
AURKA hgnc:11393 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AURKA (hgnc:11393). hgnc:11393 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
MYC Protein Accumulation The sub-network was identified by its activity toward MYC oncoproteins; the intermediate steps between the kinases and the protein pool are partly mapped and partly not.
Show evidence (3 references)
PMID:36692000 SUPPORT In Vitro
"Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins."
Identifies the AURKA/GSK3 sub-network this node names.
PMID:26489647 SUPPORT Human Clinical
"Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples."
Independent transcriptomic confirmation that Aurora kinase A is raised in human tumours.
PMID:32154962 SUPPORT Human Clinical
"The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA)."
The trial report's own statement of the rationale, which is how this node became a drug target rather than only a phosphoproteomic observation.
MYC Protein Accumulation
c-MYC protein rises in fibrolamellar carcinoma cells. The dominant route is translational rather than transcriptional: blocking translation initiation with an eIF4A inhibitor collapsed MYC expression and cell growth, which is the observation that separates this node from a transcriptional MYC amplification.
MYC hgnc:7553 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYC (hgnc:7553). hgnc:7553 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Hepatocyte Transformation and Clonal Proliferation
Ornithine Transcarbamylase Suppression Raised c-Myc is the proposed driver of the ornithine decarboxylase increase that in turn suppresses ornithine transcarbamylase.
Show evidence (2 references)
PMID:36692000 SUPPORT In Vitro
"the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin"
Establishes both that MYC protein rises and that the route is translational, which is the specific claim this node makes.
PMID:36692000 SUPPORT In Vitro
"This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro."
The pharmacological test in a fibrolamellar carcinoma line, which is what ties this node to growth rather than leaving it a signalling observation.
Wnt/beta-Catenin Cooperation
The fusion kinase interacts with beta-catenin, and activating beta-catenin genetically markedly increases tumour formation in mouse models. Recurrent Wnt pathway mutations in human tumours support this as a real cooperating route. It is curated as cooperation, not as a second required driver - the fusion alone suffices.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Transposon-mediated DNAJB1-PRKACA mouse with beta-catenin activation Mouse recapitulates Genetic beta-catenin activation significantly enhanced fusion-driven tumorigenesis.
Downstream
Hepatocyte Transformation and Clonal Proliferation
Show evidence (1 reference)
PMID:29162699 SUPPORT Model Organism
"Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC"
Establishes both the mouse cooperation effect and its human genomic correlate, which is what this node claims.
Hepatocyte Transformation and Clonal Proliferation
The convergent consequence is transformation of hepatocytes in a liver with no underlying disease. The fusion is sufficient on its own: engineering it into adult mouse liver, with no other engineered alteration and no carcinogen exposure, produces tumours resembling human fibrolamellar carcinoma, while overexpressing wild-type PRKACA does not.
neoplastic hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neoplastic hepatocyte, annotated with hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Patient-derived fibrolamellar carcinoma organoids ORGANOID The organoids reproduce the histology, immunohistochemistry and transcriptome of the tumours they came from.
Animal models
CRISPR/Cas9 Dnajb1-Prkaca fusion mouse Mouse recapitulates The fusion alone produced neoplasms in 12 of 15 mice and none of 11 controls, with histologic and cytologic features of human tumours.
zfDnaJa-Pkaca hepatocyte-expressing zebrafish Zebrafish partially recapitulates Fusion expression enlarges the liver and the hepatocytes in it, with an early neutrophil and macrophage infiltrate.
Downstream
Lamellar Fibrous Stroma Formation The tumour induces its characteristic stroma, but the steps between transformation and lamellar collagen deposition are not established.
Hepatic Mass in a Non-Cirrhotic Liver
Show evidence (2 references)
PMID:28923495 SUPPORT Model Organism
"Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms."
The sufficiency experiment, with its control arm, that makes this node a demonstrated consequence rather than an inferred one.
PMID:29162699 SUPPORT Model Organism
"overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression"
The negative control that distinguishes a neomorphic fusion from simple PKA overactivity - the entry's central mechanistic claim.
Lamellar Fibrous Stroma Formation
Parallel bands of collagen encircle nests of tumour cells, producing the architecture the disease is named for. This is a tumour-induced stroma distinct from cirrhotic fibrosis, and the tumour arises in a liver that is not otherwise fibrotic. The cellular route from transformed hepatocyte to lamellar collagen is not established, so it is modelled as an edge with unknown intermediates rather than asserted.
Hepatic Mass in a Non-Cirrhotic Liver
A large liver mass in a patient with no cirrhosis and none of the risk factors that precede conventional hepatocellular carcinoma. Because the symptoms are nonspecific and the patients are young and otherwise well, a substantial fraction present with a large tumour burden and locally invasive or metastatic disease.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:39326063 SUPPORT Other
"Patients typically lack cirrhosis or other risk factors and present with a large tumor burden and locally invasive or metastatic disease"
States both the absent-risk-factor context and the advanced stage at presentation.
Ornithine Transcarbamylase Suppression
Tumour tissue shows raised Aurora kinase A, c-MYC and ornithine decarboxylase with reduced ornithine transcarbamylase. Suppressing a urea cycle enzyme is how a liver tumour comes to phenocopy an inborn error of metabolism.
OTC hgnc:8512 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves OTC (hgnc:8512). hgnc:8512 is a gene from the HUGO Gene Nomenclature Committee. ODC1 hgnc:8109 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ODC1 (hgnc:8109). hgnc:8109 is a gene from the HUGO Gene Nomenclature Committee.
urea cycle GO:0000050 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased urea cycle (GO:0000050). GO:0000050 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hyperammonemic Encephalopathy
Show evidence (1 reference)
PMID:36788919 SUPPORT Human Clinical
"Fibrolamellar carcinoma and adenomyomatosis samples presented increased expression of Aurora kinase A, c-MYC, and ornithine decarboxylase when compared to normal liver, while ornithine transcarbamylase was decreased."
Measures every enzyme in the proposed chain in human tumour tissue, which is what this node records.
Hyperammonemic Encephalopathy
A paraneoplastic encephalopathy driven by the tumour's own suppression of urea cycle capacity rather than by liver failure. It is the reason a fibrolamellar carcinoma patient can present looking like a urea cycle disorder while their non-tumour liver function is preserved.
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Histopathology

2
Lamellar Fibrous Bands
Parallel collagen bands encircling nests of tumour cells, the feature the disease is named for.
Large Eosinophilic Mitochondria-Rich Polygonal Cells
Large polygonal tumour cells with granular eosinophilic, mitochondria-rich cytoplasm.
Show evidence (1 reference)
PMID:28923495 SUPPORT Model Organism
"large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes"
Describes the cytology this finding records, quoted from the mouse-model paper's description of tumours reproducing the human histology.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Fibrolamellar Hepatocellular Carcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Breast 1
Gynecomastia HP:0000771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gynecomastia (HP:0000771). HP:0000771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41178855 SUPPORT Human Clinical
"Less frequent but notable clinical findings include gynecomastia in males, fulminant hepatic failure, recurrent episodes of deep vein thrombosis, hepatic encephalopathy, thrombophlebitis of the lower extremities, anemia, ascites, and hypoglycemia"
Places gynecomastia explicitly in the less-frequent tier, which is how this phenotype is curated.
Digestive 4
Liver Mass Without Cirrhosis Neoplasm of the liver HP:0002896 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm of the liver (HP:0002896). HP:0002896 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24578576 SUPPORT Human Clinical
"Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis."
States the defining clinical context of this phenotype.
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Abdominal Distension Abdominal distention HP:0003270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal distention (HP:0003270). HP:0003270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41178855 SUPPORT Human Clinical
"Presenting symptoms are often vague and include nonspecific abdominal pain, nausea, abdominal distension or fullness, constitutional symptoms such as malaise, and unintentional weight loss."
Lists abdominal distension among the presenting symptoms. Quoted from a narrative review of the clinical series; no frequency is attached because the source gives none.
Jaundice HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41178855 SUPPORT Human Clinical
"On physical examination, patients may exhibit hepatomegaly or a palpable abdominal mass, which may be associated with or without right upper quadrant tenderness and obstructive jaundice."
Names obstructive jaundice as an examination finding, qualified as variable in the source itself.
Metabolism 2
Hyperammonemia HP:0001987 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperammonemia (HP:0001987). HP:0001987 is a phenotype from the Human Phenotype Ontology.
Normal Serum Alpha-Fetoprotein Elevated circulating alpha-fetoprotein concentration HP:0006254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating alpha-fetoprotein concentration (HP:0006254). HP:0006254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24578576 REFUTE Human Clinical
"Patients have normal levels of alpha fetoprotein without underlying liver disease or history of viral hepatitis"
Graded REFUTE against the bound HP term, which names *elevated* AFP. The finding in this disease is a normal value, and the evidence direction records that rather than letting the term imply the opposite.
Nervous System 1
Encephalopathy HP:0001298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Encephalopathy (HP:0001298). HP:0001298 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36788919 SUPPORT Other
"Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma."
Establishes the association and its severity.
Constitutional 1
Abdominal Pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Growth 1
Weight Loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
🧬

Genetic Associations

1
DNAJB1-PRKACA
Gene: PRKACA hgnc:9380 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRKACA (hgnc:9380). hgnc:9380 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (2 references)
PMID:24578576 SUPPORT Human Clinical
"Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis."
The founding recurrence figure.
PMID:25605237 SUPPORT Human Clinical
"The lack of a second-hit mutation in the genomic landscape of fibrolamellar hepatocellular carcinoma makes the DNAJB1-PRKACA fusion protein the best target for diagnostic and therapeutic advancements."
Establishes the absence of a recurrent cooperating lesion, which is why this entry treats the fusion as the driver rather than one of several.
💊

Medical Actions

6
Surgical Resection
Action: HepatectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hepatectomy (NCIT:C15249). NCIT:C15249 is a clinical intervention from the NCI Thesaurus. NCIT:C15249
Platform: Surgery
Hepatectomy is the mainstay and the only modality with a demonstrated survival effect in population data. Patients not treated surgically had roughly three times the risk of death.
Mechanism Target:
Hepatic Mass in a Non-Cirrhotic Liver — Resection removes the tumour bulk; because the background liver is not cirrhotic, more of it can be taken than in conventional hepatocellular carcinoma.
Show evidence (1 reference)
PMID:32052215 SUPPORT Human Clinical
"Patients who were not treated with surgical intervention had about 3 times increased risk for death (HR 2.8, 95% CI 1.68-4.72, P = 0.000)."
The population-based effect estimate this treatment rests on.
Cytotoxic Chemotherapy
Action: ChemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. NCIT:C15632
Platform: Small molecule
Curated as a treatment that does not work. Chemotherapy is given to nearly half of patients in population data yet has no measurable effect on outcome, and the tumours were described as poorly chemoresponsive from the founding report onward. Recording the negative result is the point.
Show evidence (2 references)
PMID:32052215 REFUTE Human Clinical
"Radiation and chemotherapy did not significantly affect outcomes."
Graded REFUTE because it contradicts the claim that this treatment benefits patients. The same sentence covers radiation.
PMID:39326063 SUPPORT Other
"There are no standard treatments for advanced FLC, and clinical trials with targeted, conventional, and immune therapies have shown limited benefit."
Supports the description's claim that no systemic option is established, across drug classes rather than only cytotoxics.
DNAJB1-PRKACA Fusion-Neoantigen Peptide Vaccine with Nivolumab and Ipilimumab
Action: VaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. NCIT:C15346
Agent: nivolumab NCIT:C68814 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses nivolumab (NCIT:C68814). NCIT:C68814 is a therapeutic agent from the NCI Thesaurus. ipilimumab NCIT:C2654 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ipilimumab (NCIT:C2654). NCIT:C2654 is a therapeutic agent from the NCI Thesaurus.
Platform: Vaccine
A synthetic long peptide spanning the fusion breakpoint, given with a poly-ICLC adjuvant and dual checkpoint blockade. This is the therapeutic payoff of the entry's single-driver framing: because the breakpoint falls inside an intron, the chimeric junction sequence is the same in every patient, so one off-the-shelf peptide is a shared neoantigen for the whole disease. Phase 1 only - the disease control figure comes from 12 evaluable patients and is not an efficacy result.
Mechanism Target:
Chimeric DNAJ-PKAc Kinase Expression — The immunogen is the chimeric junction itself, so the treatment targets the driver lesion directly rather than a downstream consequence of it.
Show evidence (4 references)
PMID:41286513 SUPPORT Human Clinical
"fusion breakpoint occurs within an intron, making the sequence of the chimera consistent across patients. This allows a single vaccine to be broadly applicable for patients with FLC."
States why a single shared peptide works for this disease - the intronic breakpoint makes the chimera's sequence identical across patients.
PMID:41286513 SUPPORT Human Clinical
"DNAJ-PKAc-specific T cell responses were detected in 9 of 12 patients after treatment."
The immunological primary endpoint, which is what a phase 1 trial is powered for.
PMID:41286513 SUPPORT Human Clinical
"In the subset of patients who completed the initial priming phase the disease control rate was 75% (9/12), with three partial responses (25%)."
The clinical signal, quoted with its own denominator. Curated as an early-phase observation, not as an efficacy claim.
+ 1 more reference
Liver Transplantation
Action: Liver TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver Transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. NCIT:C15271
Platform: Surgery
Considered for liver-confined disease that cannot be resected. Reported five-year survival spans a wide range across series, and the individual reports make clear that nodal and vascular involvement drive the outcome rather than the transplant itself.
Mechanism Target:
Hepatic Mass in a Non-Cirrhotic Liver — Total hepatectomy with grafting removes tumour that partial resection cannot clear, at the cost of lifelong immunosuppression.
Show evidence (2 references)
PMID:41178855 SUPPORT Human Clinical
"A systematic review of 35 series involving 575 patients indicated a 5-year survival rate ranging from 29% to 55% for those undergoing liver transplantation"
The pooled survival range across 35 series. Quoted as a range rather than a point estimate because that is how the source reports it.
PMID:29633928 SUPPORT Human Clinical
"Our patient, with poor prognostic criteria such as hilar lymph node metastasis, microvascular invasion, and poor differentiation, had 22 months of tumor-free survival and 26 months of overall survival after having undergone living-donor liver transplant."
A single case, curated for what it shows about the limits of the procedure: hilar nodal metastasis and microvascular invasion were present and the patient died at 26 months. One case is weak evidence and is recorded as such.
Regional Lymph Node Sampling
Action: LymphadenectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Lymphadenectomy (NCIT:C15275). NCIT:C15275 is a clinical intervention from the NCI Thesaurus. NCIT:C15275
Platform: Surgery
Curated because the evidence points two ways and both directions matter. Fibrolamellar histology independently predicts node positivity, so sampling is informative for staging; but in the same cohort, sampling itself carried no independent survival benefit. This entry records the staging rationale and the absent survival effect as separate evidence items rather than resolving them into a recommendation.
Show evidence (2 references)
PMID:35398630 SUPPORT Human Clinical
"FLC was an independent risk factor for LN positivity, suggesting a role for routine LN sampling in these patients."
The staging rationale: this histology is itself a predictor of positive nodes, which is the study's argument for sampling.
PMID:35398630 REFUTE Human Clinical
"In AYA patients with HCC, LN sampling was not associated with an independent survival benefit."
Graded REFUTE against a survival-benefit claim, which the deep-research report asserted and this cohort does not support. The same paper supplies both items because it makes both findings.
Aurora Kinase A Inhibition
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
ENMD-2076, an oral Aurora A inhibitor, was the first drug taken into a trial on the strength of this entry's own mechanism - AURKA overexpression downstream of the fusion. It is curated because it did not work. A single partial response in 35 patients is the counterexample to reading a phosphoproteomic node as a validated drug target.
Mechanism Target:
AURKA-GSK3 Sub-Network Activation — The drug targets Aurora kinase A, which is the node's own gene product.
Show evidence (2 references)
PMID:32154962 REFUTE Human Clinical
"The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent."
Graded REFUTE against the claim that this treatment benefits patients. The response and stable-disease figures are quoted with the trial's own conclusion attached to them.
PMID:32154962 REFUTE Human Clinical
"The study provided no rationale for further studying ENMD-2076 as a single agent in FLC."
The trial's formal conclusion, quoted separately from the numbers behind it.
🔬

Biochemical Markers

1
Serum unsaturated vitamin B12 binding capacity (INCREASED)
Context: The classic serum marker of this tumour, and the historical counterpart to the normal alpha-fetoprotein: in the founding 1982 series every patient with a raised value had a normal alpha-fetoprotein and no cirrhosis. It is a correlation established in a small cohort and has not displaced imaging or fusion testing in practice, so it is curated as a supporting laboratory finding rather than a diagnostic test.
Show evidence (2 references)
PMID:6288165 SUPPORT Human Clinical
"Seven of the 10 patients had fibrolamellar hepatocellular carcinoma, a recently recognised histological variant, which was found in only one young patient without increased serum unsaturated vitamin B12 binding capacity and no alpha-fetoprotein among the remaining 97."
The enrichment result: seven of ten patients with a raised value had this histology, against one case among the other 97 patients.
PMID:6288165 SUPPORT Human Clinical
"This high degree of correlation between increased serum unsaturated vitamin B12 binding capacity and fibrolamellar hepatocellular carcinoma has not been reported before."
The authors' own framing of the finding as a correlation, which is the strength this entry claims for it.
🔬

Diagnosis

3
DNAJB1-PRKACA Fusion Detection
RT-PCR, FISH for PRKACA rearrangement, or RNA in situ hybridisation. The fusion is the diagnostic test because it is both near-universal in this tumour and absent from the tumours that mimic it - including scirrhous hepatocellular carcinoma, the closest histologic mimic.
Show evidence (3 references)
PMID:25698061 SUPPORT Human Clinical
"the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in other tumor types"
The specificity result across 106 liver tumours that makes fusion detection diagnostic rather than merely supportive.
PMID:25698061 SUPPORT Human Clinical
"Rearrangements of the PRKACA locus was seen in all 19 fibrolamellar carcinoma specimens, but in none of the scirrhous hepatocellular carcinomas."
Separates the tumour from its closest histologic mimic, which is the discrimination the test is used for.
PMID:31676785 REFUTE Human Clinical
"Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present."
Graded REFUTE against an unqualified reading of this test as diagnostic. A Memorial Sloan Kettering series found the same fusion in six oncocytic pancreatobiliary neoplasms, so the specificity established above holds across liver tumours but not across all anatomic sites. The two items are not in conflict - they were asked in different populations - and both are kept.
Cross-Sectional Imaging - Central Stellate Scar with Calcification
A large hypervascular hepatic mass with a central non-enhancing stellate scar, usually containing calcification. The combination is the practical imaging signature and is what first raises the diagnosis in a young patient with a normal alpha-fetoprotein.
Show evidence (3 references)
PMID:29948061 SUPPORT Human Clinical
"Central stellate scar was present in 73% (24/33). In FLHCC having central stellate scar, calcification within the central scar was seen in 88% (21/24)."
The frequencies from a 33-patient multiphasic CT series: the scar in about three quarters of tumours, and calcification within it in most of those that have one.
PMID:29948061 SUPPORT Human Clinical
"Central stellate scar with internal calcification is a useful imaging feature that can help in the diagnosis of FLHCC."
The series' own statement that this combination is diagnostically useful.
PMID:41178855 SUPPORT Human Clinical
"A central stellate scar is present in approximately 65%-70% of cases, and calcifications - often located within this scar - are observed in 40%-68% of patients."
A second, wider set of figures for the same two features. Curated alongside the CT series rather than merged with it - 65-70% and 73% are different populations, not a disagreement to average away.
CK7 and CD68 Immunohistochemistry
Co-expression of cytokeratin 7 and CD68 on the tumour cells, which with compatible morphology is treated as diagnostic. Neither marker alone is specific; the pair is the useful test, and CD68 is what separates this tumour from its closest histologic mimic.
Show evidence (4 references)
PMID:26712049 SUPPORT Human Clinical
"Immunohistochemically, all cases were positive for CK7 and for CD68 (n=4)."
The staining result in every case of the series, for both markers.
PMID:26712049 SUPPORT Human Clinical
"CD68 immunostaining is a sensitive marker for FL-HCC that may be of use in routine diagnostic surgical pathology. Lack of CD68 staining should suggest caution in making a diagnosis of FL-HCC."
States the test's sensitivity claim and, importantly, how a negative result should be read.
PMID:35803261 SUPPORT In Vitro
"when used in conjunction, along with compatible morphology, co-expression of CK7 and CD68 is diagnostic of FLC"
States the conjunction requirement explicitly - it is the co-expression plus morphology that is diagnostic, not either stain on its own.
+ 1 more reference
📈

Progression

3
Population-Based Survival
SEER cause-specific survival is 72.0% at one year and 32.9% at five, with a median of 32.9 months - roughly three times the 11.7-month median for conventional hepatocellular carcinoma in the same analysis.
Show evidence (1 reference)
PMID:32052215 SUPPORT Human Clinical
"One- and 5-year cause-specific survival for FLC was 72.0% and 32.9%, respectively, with a median survival of 32.9 months."
The all-stage survival figures this phase records.
Advanced Disease
Five-year overall survival is under 10% once disease is advanced. This is not in conflict with the SEER figure above: that one is all-stage and cause-specific, this one is restricted to advanced disease. The two are recorded separately rather than reconciled.
Show evidence (1 reference)
PMID:39326063 SUPPORT Other
"Outcomes are poor for advanced disease, with a 5-year overall survival of less than 10%"
The advanced-disease survival figure, whose population differs from the SEER record above.
Recurrence After Resection
Recurrence after a curative-intent resection is the rule rather than the exception, and re-resecting it is worth doing. The reported recurrence fraction ranges from most of a small single-centre series to all patients in a pooled relapse review, so the entry records the sources separately rather than settling on one number. Reported survival after re-resection is substantially longer than without, which is why an aggressive surgical posture persists at relapse.
Show evidence (3 references)
PMID:32397993 SUPPORT Human Clinical
"Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection."
A single-centre surgical series: five of eight patients recurred at a median of nine months, and a quarter went on to a second resection.
PMID:41178855 SUPPORT Human Clinical
"found that all patients experienced recurrence after initial surgery, with a median time to recurrence of 2.2 years. For those who underwent re-resection, the median OS increased to 4.7 years, with a 5-year survival rate of 48%."
A pooled relapse review reporting universal recurrence and the survival gain from re-resection. Kept separate from the single-centre figures above rather than averaged with them.
PMID:41178855 SUPPORT Human Clinical
"Case series have demonstrated that re-resection of recurrent FLHCC lesions can lead to improved survival outcomes, with median OS extending up to 122 months in some cases"
The upper end of the reported re-resection survival, quoted with the source's own hedge that it is what case series have shown in some cases.
📊

Prevalence

1
United States, SEER 2000-2016
Annual Incidence 0.02 per 100,000 per year <1 in 1,000,000 per year
Age-adjusted incidence from 300 SEER-registered cases.
Show evidence (1 reference)
PMID:32052215 SUPPORT Human Clinical
"The overall age-adjusted incidence of FLC between 2000 and 2016 was 0.02 per 100,000 per year."
The population-based incidence figure this record normalizes.
🌍

Epidemiology

1
Young Age at Diagnosis
Median age at diagnosis is 27, decades below conventional hepatocellular carcinoma. The SEER distribution is bimodal, with a second peak in the eighth decade that is less often emphasised in the clinical literature.
Show evidence (2 references)
PMID:32052215 SUPPORT Human Clinical
"Median age at diagnosis was 27 ± 22 years."
The median age this record reports.
PMID:32052215 SUPPORT Human Clinical
"A bimodal distribution was observed where the highest incidences occurred between 15-19 years and 70-74 years."
The bimodality, which the "adolescents and young adults" framing common elsewhere in the literature omits.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Fibrolamellar Hepatocellular Carcinoma:

Scirrhous Hepatocellular Carcinoma
Overlapping Features The closest histologic mimic, sharing a fibrous stroma. PRKACA rearrangement testing separates them cleanly.
Show evidence (1 reference)
PMID:25698061 SUPPORT Human Clinical
"FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas, which can closely mimic fibrolamellar carcinoma."
Names the mimic and the assay used to distinguish it.
Conventional Hepatocellular Carcinoma
Overlapping Features Distinguished by patient age, absent cirrhosis and risk factors, normal alpha-fetoprotein, and a genomic landscape that whole-genome sequencing shows to be different.
Show evidence (1 reference)
PMID:25605237 SUPPORT Human Clinical
"The mutations, altered pathways and structural variants that characterized fibrolamellar hepatocellular carcinoma were distinct from those in hepatocellular carcinoma, further defining it as a distinct carcinoma."
The genomic argument that this is a separate entity rather than an HCC variant - the basis for curating it as its own entry.
Focal Nodular Hyperplasia
Overlapping Features The benign lesion this tumour is most often mistaken for on imaging, because both carry a central scar. The error matters in a specific direction: patients under surveillance for a presumed focal nodular hyperplasia have presented later with advanced fibrolamellar carcinoma. The scar's T2 signal and the presence of calcification are what separate them.
Show evidence (2 references)
PMID:32397993 SUPPORT Human Clinical
"Due to some radiomorphological similarities with focal nodular hyperplasia (FNH) (both may present with a stellate central scar), FL-HCC can be misinterpreted as FNH"
Names the shared feature and states the direction of the misdiagnosis.
PMID:41178855 SUPPORT Human Clinical
"The fibrous stroma within the tumor, particularly the central scar, is hypointense on both T1- and T2-weighted images - unlike in focal nodular hyperplasia, where the scar is usually hyperintense on T2."
The MRI feature that discriminates them: the scar is T2-hypointense here and T2-hyperintense in focal nodular hyperplasia.
🔬

Clinical Trials

4
NCT04248569 PHASE_I ACTIVE_NOT_RECRUITING
Pilot trial of the DNAJB1-PRKACA fusion kinase peptide vaccine with nivolumab and ipilimumab in unresectable or metastatic disease. Published as a phase 1 report in 2025.
Show evidence (1 reference)
clinicaltrials:NCT04248569 SUPPORT Other
"The primary objective of the trial is the safety and tolerability of administering a vaccine targeting the DNAJB1-PRKACA fusion kinase, in combination with nivolumab and ipilimumab in patients with unresectable or metastatic FLC and with non-FLC solid tumors and to assess the T-cell response."
The registry record establishing the trial's design and endpoints. Graded OTHER because a registration document is not itself study evidence; the results are curated on the treatment from PMID:41286513.
NCT02234986 PHASE_II COMPLETED
Multicentre open-label phase 2 of oral ENMD-2076 in advanced disease. Completed and published - one partial response in 35 patients, and the investigators concluded against further single-agent development.
Show evidence (1 reference)
clinicaltrials:NCT02234986 SUPPORT Other
"The purpose of the study is to determine whether once-daily dosing with ENMD-2076 will be a safe and effective treatment in patients with FLC. Safety will be measured by looking at the adverse events that may happen and the efficacy will look at the progression of the disease over time."
The registry record for the trial whose published results are curated on the Aurora Kinase A Inhibition treatment.
NCT04380545 PHASE_II RECRUITING
Phase I/II of nivolumab with fluorouracil and interferon alfa-2b in unresectable disease.
Show evidence (1 reference)
clinicaltrials:NCT04380545 SUPPORT Other
"This phase I/II trial studies the side effects and how well nivolumab, fluorouracil, and interferon alpha 2b work for the treatment of fibrolamellar cancer (liver cell cancer) that cannot be removed by surgery (unresectable)."
The registry record. No results are published, so nothing is curated as a treatment on the strength of it.
NCT06620302 PHASE_I RECRUITING
Phase I with a phase II feasibility cohort for fibrolamellar carcinoma, testing the Bcl-xL degrader DT2216 with irinotecan in relapsed or refractory paediatric and young-adult solid tumours.
Show evidence (1 reference)
clinicaltrials:NCT06620302 SUPPORT Other
"This phase I/II trial tests the safety, side effects and best dose of DT2216 in combination with irinotecan and how well it works in treating children, adolescents and young adults with solid tumors and fibrolamellar cancer that has come back after a period of improvement (relapsed) or that has..."
The registry record. Listed because the disease has a named feasibility cohort in it, not because any result is available.
🧫

Experimental Models

2
Patient-derived fibrolamellar carcinoma organoids ORGANOID
Twenty-one organoid lines grown from nine patients - primary tumour, metastases, and matched non-tumour liver from the same operations. The matched normal lines are what make this a comparison rather than a culture collection, and the panel was taken through a drug screen.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:35803261
Pathograph links
Hepatocyte Transformation and Clonal Proliferation recapitulates fidelity: moderate observes: cellular The organoids reproduce the histology, immunohistochemistry and transcriptome of the tumours they came from.
Limitations: An organoid has no stroma, so nothing about the lamellar fibrous bands - the feature the disease is named for - can be studied in it. Seven of the nine donors had received chemotherapy before resection, so the lines are not uniformly treatment-naive.
Show evidence (2 references)
PMID:35803261 SUPPORT In Vitro
"These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor."
The fidelity claim, across three independent kinds of comparison.
+ 1 more reference
AML12 DNAJ-PKAc gene-edited hepatocyte line CELL_LINE
Mouse hepatocytes gene-edited to express DNAJ-PKAc, used for the phosphoproteomics and drug screening that defined the Hsp70/AKAP-Lbc scaffolding mechanism.
Organism
mouse NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in mouse, annotated with Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Publication
PMID:31063128
Pathograph links
Acquired Hsp70 Scaffolding Function recapitulates fidelity: moderate observes: molecular The line reproduces the fusion's Hsp70 recruitment and ERK-biased signalling, and its proliferation is selectively blocked by Hsp70 plus MEK inhibitor combinations.
Limitations: A mouse hepatocyte line reports the signalling consequences of the fusion but not the tissue architecture, stroma or clinical course; nothing about the lamellar fibrosis can be learned from it.
Show evidence (1 reference)
PMID:31063128 SUPPORT In Vitro
"Drug screening reveals Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12DNAJ-PKAc cells."
Selective dependence on the scaffolding partners establishes the line as informative for this node.
🐁

Animal Models

3
CRISPR/Cas9 Dnajb1-Prkaca fusion mouse
CRISPR/Cas9 vectors delivered by hydrodynamic tail vein injection to adult FVB/N mouse liver, juxtaposing Dnajb1 exon 1 with Prkaca exon 2. The mice carried no other engineered alteration and were exposed to no liver toxin or carcinogen, which is what makes this a sufficiency experiment rather than a cooperation one.
Species
Mouse
Genotype
Dnajb1-Prkaca fusion engineered by CRISPR/Cas9 deletion of the syntenic chromosome 8 region
Publication
PMID:28923495
Pathograph links
Hepatocyte Transformation and Clonal Proliferation recapitulates fidelity: high observes: organism The fusion alone produced neoplasms in 12 of 15 mice and none of 11 controls, with histologic and cytologic features of human tumours.
Limitations: Tumours are described as indolent in the companion model, and the 14-month latency is long relative to the human disease course, so the model reproduces initiation better than it reproduces tempo.
Show evidence (1 reference)
PMID:28923495 SUPPORT Model Organism
"Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms."
The controlled result establishing this model as informative for the transformation node.
Transposon-mediated DNAJB1-PRKACA mouse with beta-catenin activation
CRISPR-Cas9 plus transposon-mediated somatic gene transfer, used both to show the fusion drives tumours and to test cooperation with beta-catenin and with hepatotoxin-induced injury.
Species
Mouse
Genotype
DNAJB1-PRKACA chimeric cDNA or endogenous fusion, with and without activated beta-catenin
Publication
PMID:29162699
Pathograph links
Wnt/beta-Catenin Cooperation recapitulates fidelity: moderate observes: organism Genetic beta-catenin activation significantly enhanced fusion-driven tumorigenesis.
Limitations: Cooperation is demonstrated in mouse; in humans the support is recurrent Wnt pathway mutations, which is an association rather than a demonstration, so the human claim is weaker than the mouse one.
Show evidence (1 reference)
PMID:29162699 SUPPORT Model Organism
"Tumorigenesis was significantly enhanced by genetic activation of β-catenin"
The cooperation result this link records.
zfDnaJa-Pkaca hepatocyte-expressing zebrafish
A larval zebrafish model expressing the zebrafish orthologue of the fusion in hepatocytes. Its point is live imaging of the earliest events, which the mouse models cannot show: the innate immune infiltrate appears before any tumour does.
Species
Zebrafish
Genotype
hepatocyte-restricted ectopic expression of zebrafish Dnaja-Pkaca
Publication
PMID:32102783
Pathograph links
Hepatocyte Transformation and Clonal Proliferation partially recapitulates fidelity: low observes: organism Fusion expression enlarges the liver and the hepatocytes in it, with an early neutrophil and macrophage infiltrate.
Limitations: A zebrafish orthologue of the fusion in larval liver is not the human chimera in an adult human liver, and the readout is hepatomegaly and inflammation rather than a lamellar-stroma tumour. It reports early events, not the disease.
Divergences from the human mechanism
species mismatch qualifying
The construct is zebrafish Dnaja-Pkaca, not human DNAJB1-PRKACA, so the chimeric junction sequence that defines the human lesion - and that the peptide vaccine targets - is not the sequence expressed here.
proxy quantity qualifying
The measured quantities are liver size, hepatocyte size and immune-cell infiltration in a larva. The node's quantity is transformation of hepatocytes into a tumour with lamellar stroma and eosinophilic polygonal cytology, neither of which this model reports.
Show evidence (2 references)
PMID:32102783 SUPPORT Model Organism
"Expression of zfDnaJa-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size."
The growth phenotype that ties this model to the transformation node.
+ 1 more reference
{ }

Source YAML

click to show 
name: Fibrolamellar Hepatocellular Carcinoma
creation_date: '2026-09-07T00:00:00Z'
description: >-
  Fibrolamellar carcinoma is a rare primary liver cancer of adolescents and
  young adults that arises in an otherwise normal, non-cirrhotic liver and
  without the viral, alcoholic or metabolic risk factors that define
  conventional hepatocellular carcinoma. Nearly every tumour carries the same
  single lesion: a somatic ~400 kb deletion on chromosome 19 that fuses exon 1
  of DNAJB1 to the catalytic domain of PRKACA, producing a chimeric protein
  kinase A catalytic subunit. That chimera is not merely more PKA - it is
  overexpressed relative to wild-type, it acquires an Hsp70-recruiting
  scaffolding function the normal kinase lacks, and overexpressing wild-type
  PRKACA does not reproduce its oncogenic effect. Engineering the equivalent
  fusion into mouse liver, with no other genetic change and no carcinogen,
  produces tumours resembling the human disease. Whole-genome sequencing finds
  no recurrent second hit, which leaves this among the closest things in solid
  oncology to a one-lesion cancer. Histologically the tumour is built of large
  eosinophilic, mitochondria-rich polygonal cells separated by the parallel
  lamellar collagen bands that give the disease its name. Surgical resection is
  the only intervention with a demonstrated survival effect; chemotherapy and
  radiation have none.
categories:
- Hepatobiliary Neoplasm
- Primary Liver Cancer
parents:
- hepatocellular carcinoma
disease_term:
  preferred_term: fibrolamellar carcinoma
  term:
    id: MONDO:0006210
    label: fibrolamellar hepatocellular carcinoma
synonyms:
- FLC
- FL-HCC
- FHCC
- fibrolamellar carcinoma
- fibrolamellar hepatocarcinoma
- liver cell fibrolamellar carcinoma
classifications:
  icdo_morphology:
    classification_value: Carcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY

pathophysiology:
- name: Chromosome 19 Deletion Creating the DNAJB1-PRKACA Fusion
  conforms_to: "sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion"
  description: >-
    A somatic heterozygous deletion of roughly 400 kb on chromosome 19 joins
    DNAJB1 in frame to PRKACA. The deletion is present in essentially every
    fibrolamellar carcinoma and in no adjacent normal liver, and whole-genome
    sequencing finds no recurrent second structural event alongside it.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DNAJB1
    term:
      id: hgnc:5270
      label: DNAJB1
  - preferred_term: PRKACA
    term:
      id: hgnc:9380
      label: PRKACA
  downstream:
  - target: Chimeric DNAJ-PKAc Kinase Expression
    causal_link_type: DIRECT
    description: >-
      The fusion transcript is translated into a chimeric protein that is
      detectable in tumour tissue and retains kinase activity.
    evidence:
    - reference: PMID:24578576
      reference_title: "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity."
      explanation: >-
        Establishes that the deletion yields an expressed, catalytically active
        protein rather than only a transcript, which is what this edge claims.
  evidence:
  - reference: PMID:24578576
    reference_title: "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a chimeric transcript that is expressed in FL-HCC but not in adjacent normal liver and that arises as the result of a ~400-kilobase deletion on chromosome 19."
    explanation: The founding observation defining this node - the deletion, its size, and its tumour restriction.
  - reference: PMID:24578576
    reference_title: "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis."
    explanation: Quantifies the near-universal recurrence on which this entry's single-driver framing rests.
  - reference: PMID:25605237
    reference_title: "The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are relatively few coding, somatic mutations in this cancer, putting it on the low end of the mutational spectrum."
    explanation: >-
      Whole-genome evidence for the low mutational burden that makes this
      lesion interpretable as the driver rather than one of many.

- name: Chimeric DNAJ-PKAc Kinase Expression
  description: >-
    The chimera carries the DNAJB1 amino-terminal chaperone-binding domain
    fused to the PRKACA catalytic domain. Its transcript is expressed about
    tenfold above wild-type PRKACA, so the tumour cell holds far more of the
    mutant kinase than of the normal one.
  biological_scale: MOLECULAR
  gene_products:
  - preferred_term: DNAJB1-PRKACA fusion protein
  molecular_functions:
  - preferred_term: cAMP-dependent protein kinase activity
    modifier: INCREASED
    term:
      id: GO:0004691
      label: cAMP-dependent protein kinase activity
  downstream:
  - target: Elevated cAMP-Stimulated PKA Activity
    causal_link_type: DIRECT
  - target: Acquired Hsp70 Scaffolding Function
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24578576
    reference_title: "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A."
    explanation: Describes the domain architecture of the chimera this node names.
  - reference: PMID:27027723
    reference_title: "Enhanced cAMP-stimulated protein kinase A activity in human fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAJB1-PRKACA was expressed 10-fold higher than the wild-type PRKACA transcript, resulting in overexpression of the mutant protein in tumors."
    explanation: Quantifies the expression imbalance between mutant and wild-type kinase.

- name: Elevated cAMP-Stimulated PKA Activity
  description: >-
    Tumours show higher cAMP-stimulated PKA catalytic activity than normal
    liver. The mutant and wild-type kinases have similar Km values, so the
    excess activity is a consequence of how much mutant kinase is present
    rather than of a changed affinity for substrate.
  biological_scale: MOLECULAR
  downstream:
  - target: AURKA-GSK3 Sub-Network Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: SIK Inactivation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27027723
    reference_title: "Enhanced cAMP-stimulated protein kinase A activity in human fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consequently, FL-HCCs possess elevated cAMP-stimulated PKA activity compared to normal livers, despite similar Kms between the mutant and wild-type kinases."
    explanation: >-
      States both the elevated activity and the Km comparison that locates the
      cause in abundance rather than in altered catalysis.

- name: Acquired Hsp70 Scaffolding Function
  description: >-
    The retained DNAJ domain lets the fusion recruit Hsp70, a property
    wild-type PKA does not have. A-kinase anchoring protein Lbc, itself
    upregulated in these tumours, clusters the resulting DNAJ-PKAc/Hsp70
    subcomplexes with a RAF-MEK-ERK module, so the fusion does not simply
    signal harder - it assembles a signalling complex the normal kinase never
    forms. This is the clearest evidence that the lesion is neomorphic rather
    than merely activating.
  biological_scale: MOLECULAR
  downstream:
  - target: ERK-Biased MAPK Signalling
    causal_link_type: DIRECT
    description: >-
      Clustering the fusion with a RAF-MEK-ERK module is what redirects the
      cell's signalling output toward ERK.
    evidence:
    - reference: PMID:31063128
      reference_title: "An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the proto-oncogene A-kinase anchoring protein-Lbc is up-regulated in FLC and functions to cluster DNAJ-PKAc/Hsp70 sub-complexes with a RAF-MEK-ERK kinase module"
      explanation: Names the scaffolding step that connects this node to ERK activation.
  evidence:
  - reference: PMID:31063128
    reference_title: "An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a unique property of this fusion enzyme is the ability to recruit heat shock protein 70 (Hsp70)"
    explanation: Establishes the acquired, wild-type-absent property this node describes.
  - reference: PMID:33370777
    reference_title: "Structural analyses of the PKA RIIβ holoenzyme containing the oncogenic DnaJB1-PKAc fusion protein reveal protomer asymmetry and fusion-induced allosteric perturbations in fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The J-domain also alters several biochemical properties of the RIIβ holoenzyme: It is easier to activate with cAMP, and the cooperativity is reduced."
    explanation: >-
      A measured consequence of the retained J-domain, independent of the
      Hsp70 result: the same domain that recruits Hsp70 also changes how the
      holoenzyme responds to cAMP. Graded IN_VITRO - the paper is a cryo-EM and
      small-angle-scattering study of purified holoenzyme, with molecular
      dynamics as one component rather than the whole method.

- name: ERK-Biased MAPK Signalling
  conforms_to: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"
  description: >-
    Phosphoproteomic profiling shows the fusion shifts the cell's signalling
    landscape toward ERK activation and engages downstream kinase cascades.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  downstream:
  - target: Hepatocyte Transformation and Clonal Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:31063128
    reference_title: "An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Phosphoproteomic profiling demonstrates that DNAJ-PKAc biases the signaling landscape toward ERK activation and engages downstream kinase cascades."
    explanation: Direct phosphoproteomic evidence for the ERK bias this node asserts.

- name: SIK Inactivation
  description: >-
    The fusion kinase inactivates the salt-inducible kinases, which act as
    tumour suppressors in this setting. This is the phosphorylation event
    itself, separate from the transcriptional consequence it releases.
  biological_scale: MOLECULAR
  downstream:
  - target: CRTC2-p300 Transcriptional Reprogramming
    causal_link_type: DIRECT
    description: >-
      Losing SIK activity is what releases the CRTC2-p300 coactivator complex;
      the source states the two steps in that order.
    evidence:
    - reference: PMID:39326063
      reference_title: "DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "DNAJB1-PRKACA-mediated inactivation of the SIK stimulates CRTC2-p300-mediated transcription to drive tumor growth."
      explanation: Gives the ordering of the two steps, which is what this edge asserts.
  evidence:
  - reference: PMID:39326063
    reference_title: "DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DNAJB1-PRKACA inactivates the SIK tumor suppressors in patient-derived FLC cells and engineered models."
    explanation: >-
      The inactivation event this node records, shown in both patient-derived
      cells and engineered models.

- name: CRTC2-p300 Transcriptional Reprogramming
  description: >-
    With SIK activity lost, the CRTC2 coactivator and the p300
    acetyltransferase drive a transcriptional program that supports tumour
    growth. This arm was defined in 2024 by combining model systems with human
    tumour specimens.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    modifier: INCREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  downstream:
  - target: Hepatocyte Transformation and Clonal Proliferation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39326063
    reference_title: "DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DNAJB1-PRKACA-mediated inactivation of the SIK stimulates CRTC2-p300-mediated transcription to drive tumor growth."
    explanation: >-
      Names the coactivator complex and connects it to growth, which is the
      claim this node carries.

- name: AURKA-GSK3 Sub-Network Activation
  description: >-
    Phosphoproteomics across PKA-activating lesions identifies an Aurora kinase
    A / GSK3 sub-network as one of two conserved signalling outputs downstream
    of the fusion. Aurora kinase A is also raised in human tumours by
    transcriptomics, and it is the target that took the first
    fusion-rationalised drug into a trial in this disease.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: AURKA
    term:
      id: hgnc:11393
      label: AURKA
  downstream:
  - target: MYC Protein Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The sub-network was identified by its activity toward MYC oncoproteins;
      the intermediate steps between the kinases and the protein pool are
      partly mapped and partly not.
    evidence:
    - reference: PMID:36692000
      reference_title: "Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we demonstrate that Aurora Kinase A (AURKA), glycogen synthase kinase (GSK)–3B and the eukaryotic Initiation Factor (eIF)–4B all link PKA and c-MYC"
      explanation: States the link between the kinases in this node and c-MYC, which is what this edge asserts.
  evidence:
  - reference: PMID:36692000
    reference_title: "Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins."
    explanation: Identifies the AURKA/GSK3 sub-network this node names.
  - reference: PMID:26489647
    reference_title: "Transcriptomic characterization of fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples."
    explanation: Independent transcriptomic confirmation that Aurora kinase A is raised in human tumours.
  - reference: PMID:32154962
    reference_title: "Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA)."
    explanation: >-
      The trial report's own statement of the rationale, which is how this node
      became a drug target rather than only a phosphoproteomic observation.

- name: MYC Protein Accumulation
  description: >-
    c-MYC protein rises in fibrolamellar carcinoma cells. The dominant route is
    translational rather than transcriptional: blocking translation initiation
    with an eIF4A inhibitor collapsed MYC expression and cell growth, which is
    the observation that separates this node from a transcriptional MYC
    amplification.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MYC
    term:
      id: hgnc:7553
      label: MYC
  downstream:
  - target: Hepatocyte Transformation and Clonal Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Ornithine Transcarbamylase Suppression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Raised c-Myc is the proposed driver of the ornithine decarboxylase
      increase that in turn suppresses ornithine transcarbamylase.
    evidence:
    - reference: PMID:36788919
      reference_title: "Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An ornithine transcarboxylase dysfunction was suggested as a result of increased ornithine decarboxylase activity induced by c-Myc overexpression."
      explanation: >-
        States the proposed c-Myc to ODC to OTC route this edge represents.
        Quoted as the source frames it, as a proposal rather than a settled fact.
  evidence:
  - reference: PMID:36692000
    reference_title: "Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin"
    explanation: >-
      Establishes both that MYC protein rises and that the route is
      translational, which is the specific claim this node makes.
  - reference: PMID:36692000
    reference_title: "Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro."
    explanation: >-
      The pharmacological test in a fibrolamellar carcinoma line, which is what
      ties this node to growth rather than leaving it a signalling observation.

- name: Wnt/beta-Catenin Cooperation
  description: >-
    The fusion kinase interacts with beta-catenin, and activating beta-catenin
    genetically markedly increases tumour formation in mouse models. Recurrent
    Wnt pathway mutations in human tumours support this as a real cooperating
    route. It is curated as cooperation, not as a second required driver -
    the fusion alone suffices.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  downstream:
  - target: Hepatocyte Transformation and Clonal Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:29162699
    reference_title: "DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC"
    explanation: >-
      Establishes both the mouse cooperation effect and its human genomic
      correlate, which is what this node claims.

- name: Hepatocyte Transformation and Clonal Proliferation
  conforms_to: "sustaining_proliferative_signaling#Growth-Factor-Independent Proliferation"
  description: >-
    The convergent consequence is transformation of hepatocytes in a liver with
    no underlying disease. The fusion is sufficient on its own: engineering it
    into adult mouse liver, with no other engineered alteration and no
    carcinogen exposure, produces tumours resembling human fibrolamellar
    carcinoma, while overexpressing wild-type PRKACA does not.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neoplastic hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Lamellar Fibrous Stroma Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The tumour induces its characteristic stroma, but the steps between
      transformation and lamellar collagen deposition are not established.
  - target: Hepatic Mass in a Non-Cirrhotic Liver
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:28923495
    reference_title: "CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms."
    explanation: >-
      The sufficiency experiment, with its control arm, that makes this node a
      demonstrated consequence rather than an inferred one.
  - reference: PMID:29162699
    reference_title: "DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression"
    explanation: >-
      The negative control that distinguishes a neomorphic fusion from simple
      PKA overactivity - the entry's central mechanistic claim.

- name: Lamellar Fibrous Stroma Formation
  description: >-
    Parallel bands of collagen encircle nests of tumour cells, producing the
    architecture the disease is named for. This is a tumour-induced stroma
    distinct from cirrhotic fibrosis, and the tumour arises in a liver that is
    not otherwise fibrotic. The cellular route from transformed hepatocyte to
    lamellar collagen is not established, so it is modelled as an edge with
    unknown intermediates rather than asserted.
  biological_scale: TISSUE

- name: Hepatic Mass in a Non-Cirrhotic Liver
  description: >-
    A large liver mass in a patient with no cirrhosis and none of the risk
    factors that precede conventional hepatocellular carcinoma. Because the
    symptoms are nonspecific and the patients are young and otherwise well, a
    substantial fraction present with a large tumour burden and locally
    invasive or metastatic disease.
  biological_scale: ORGANISM
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:39326063
    reference_title: "DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients typically lack cirrhosis or other risk factors and present with a large tumor burden and locally invasive or metastatic disease"
    explanation: States both the absent-risk-factor context and the advanced stage at presentation.

- name: Ornithine Transcarbamylase Suppression
  description: >-
    Tumour tissue shows raised Aurora kinase A, c-MYC and ornithine
    decarboxylase with reduced ornithine transcarbamylase. Suppressing a urea
    cycle enzyme is how a liver tumour comes to phenocopy an inborn error of
    metabolism.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: OTC
    term:
      id: hgnc:8512
      label: OTC
  - preferred_term: ODC1
    term:
      id: hgnc:8109
      label: ODC1
  biological_processes:
  - preferred_term: urea cycle
    modifier: DECREASED
    term:
      id: GO:0000050
      label: urea cycle
  downstream:
  - target: Hyperammonemic Encephalopathy
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36788919
    reference_title: "Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibrolamellar carcinoma and adenomyomatosis samples presented increased expression of Aurora kinase A, c-MYC, and ornithine decarboxylase when compared to normal liver, while ornithine transcarbamylase was decreased."
    explanation: >-
      Measures every enzyme in the proposed chain in human tumour tissue, which
      is what this node records.

- name: Hyperammonemic Encephalopathy
  description: >-
    A paraneoplastic encephalopathy driven by the tumour's own suppression of
    urea cycle capacity rather than by liver failure. It is the reason a
    fibrolamellar carcinoma patient can present looking like a urea cycle
    disorder while their non-tumour liver function is preserved.
  biological_scale: ORGANISM

phenotypes:
- category: Hepatic
  name: Liver Mass Without Cirrhosis
  description: >-
    A hepatic mass arising in a liver with no cirrhosis and no viral, alcoholic
    or metabolic risk factor - the presentation that separates this tumour from
    conventional hepatocellular carcinoma at first contact.
  phenotype_term:
    preferred_term: Neoplasm of the liver
    term:
      id: HP:0002896
      label: Neoplasm of the liver
  diagnostic: true
  reports_on:
  - target: Hepatic Mass in a Non-Cirrhotic Liver
    relationship: READOUT_OF
  evidence:
  - reference: PMID:24578576
    reference_title: "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis."
    explanation: States the defining clinical context of this phenotype.

- category: Neurologic
  name: Hyperammonemia
  description: >-
    Raised blood ammonia arising from the tumour's suppression of urea cycle
    capacity, not from hepatic failure.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  reports_on:
  - target: Ornithine Transcarbamylase Suppression
    relationship: READOUT_OF

- category: Neurologic
  name: Encephalopathy
  description: Altered mental status accompanying the hyperammonemia.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  reports_on:
  - target: Hyperammonemic Encephalopathy
    relationship: READOUT_OF
  evidence:
  - reference: PMID:36788919
    reference_title: "Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma."
    explanation: Establishes the association and its severity.

- category: Constitutional
  name: Abdominal Pain
  description: A common and nonspecific presenting symptom.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain

- category: Constitutional
  name: Weight Loss
  description: Unintentional weight loss at presentation.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss

- category: Hepatic
  name: Hepatomegaly
  description: Liver enlargement from tumour bulk.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly

- category: Laboratory
  name: Normal Serum Alpha-Fetoprotein
  description: >-
    Alpha-fetoprotein is characteristically normal, unlike in conventional
    hepatocellular carcinoma. Curated because its *absence* is the
    discriminating observation - a normal AFP in a young patient with a liver
    mass argues for this diagnosis rather than against a tumour.
  phenotype_term:
    preferred_term: Elevated circulating alpha-fetoprotein concentration
    term:
      id: HP:0006254
      label: Elevated circulating alpha-fetoprotein concentration
  evidence:
  - reference: PMID:24578576
    reference_title: "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients have normal levels of alpha fetoprotein without underlying liver disease or history of viral hepatitis"
    explanation: >-
      Graded REFUTE against the bound HP term, which names *elevated* AFP. The
      finding in this disease is a normal value, and the evidence direction
      records that rather than letting the term imply the opposite.

- category: Constitutional
  name: Abdominal Distension
  description: >-
    Abdominal distension or fullness, one of the vague presenting complaints
    that delays recognition of the tumour.
  phenotype_term:
    preferred_term: Abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presenting symptoms are often vague and include nonspecific abdominal pain, nausea, abdominal distension or fullness, constitutional symptoms such as malaise, and unintentional weight loss."
    explanation: >-
      Lists abdominal distension among the presenting symptoms. Quoted from a
      narrative review of the clinical series; no frequency is attached because
      the source gives none.

- category: Hepatic
  name: Jaundice
  description: >-
    Obstructive jaundice, found on examination in a minority of patients and
    not part of the typical presentation.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On physical examination, patients may exhibit hepatomegaly or a palpable abdominal mass, which may be associated with or without right upper quadrant tenderness and obstructive jaundice."
    explanation: >-
      Names obstructive jaundice as an examination finding, qualified as
      variable in the source itself.

- category: Endocrine
  name: Gynecomastia
  description: >-
    Gynecomastia in male patients, listed among the less frequent findings.
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Less frequent but notable clinical findings include gynecomastia in males, fulminant hepatic failure, recurrent episodes of deep vein thrombosis, hepatic encephalopathy, thrombophlebitis of the lower extremities, anemia, ascites, and hypoglycemia"
    explanation: >-
      Places gynecomastia explicitly in the less-frequent tier, which is how
      this phenotype is curated.

histopathology:
- name: Lamellar Fibrous Bands
  description: >-
    Parallel collagen bands encircling nests of tumour cells, the feature the
    disease is named for.
  finding_term:
    preferred_term: lamellar fibrous bands
  diagnostic: true

- name: Large Eosinophilic Mitochondria-Rich Polygonal Cells
  description: >-
    Large polygonal tumour cells with granular eosinophilic, mitochondria-rich
    cytoplasm.
  finding_term:
    preferred_term: large polygonal cells with granular eosinophilic cytoplasm
  evidence:
  - reference: PMID:28923495
    reference_title: "CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes"
    explanation: >-
      Describes the cytology this finding records, quoted from the mouse-model
      paper's description of tumours reproducing the human histology.

diagnosis:
- name: DNAJB1-PRKACA Fusion Detection
  description: >-
    RT-PCR, FISH for PRKACA rearrangement, or RNA in situ hybridisation. The
    fusion is the diagnostic test because it is both near-universal in this
    tumour and absent from the tumours that mimic it - including scirrhous
    hepatocellular carcinoma, the closest histologic mimic.
  evidence:
  - reference: PMID:25698061
    reference_title: "DNAJB1-PRKACA is specific for fibrolamellar carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in other tumor types"
    explanation: >-
      The specificity result across 106 liver tumours that makes fusion
      detection diagnostic rather than merely supportive.
  - reference: PMID:25698061
    reference_title: "DNAJB1-PRKACA is specific for fibrolamellar carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rearrangements of the PRKACA locus was seen in all 19 fibrolamellar carcinoma specimens, but in none of the scirrhous hepatocellular carcinomas."
    explanation: >-
      Separates the tumour from its closest histologic mimic, which is the
      discrimination the test is used for.
  - reference: PMID:31676785
    reference_title: "DNAJB1-PRKACA fusions occur in oncocytic pancreatic and biliary neoplasms and are not specific for fibrolamellar hepatocellular carcinoma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present."
    explanation: >-
      Graded REFUTE against an unqualified reading of this test as diagnostic.
      A Memorial Sloan Kettering series found the same fusion in six oncocytic
      pancreatobiliary neoplasms, so the specificity established above holds
      across liver tumours but not across all anatomic sites. The two items are
      not in conflict - they were asked in different populations - and both are
      kept.

- name: Cross-Sectional Imaging - Central Stellate Scar with Calcification
  description: >-
    A large hypervascular hepatic mass with a central non-enhancing stellate
    scar, usually containing calcification. The combination is the practical
    imaging signature and is what first raises the diagnosis in a young patient
    with a normal alpha-fetoprotein.
  evidence:
  - reference: PMID:29948061
    reference_title: "Fibrolamellar hepatocellular carcinoma: multiphasic CT features of the primary tumor on pre-therapy CT and pattern of distant metastases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Central stellate scar was present in 73% (24/33). In FLHCC having central stellate scar, calcification within the central scar was seen in 88% (21/24)."
    explanation: >-
      The frequencies from a 33-patient multiphasic CT series: the scar in
      about three quarters of tumours, and calcification within it in most of
      those that have one.
  - reference: PMID:29948061
    reference_title: "Fibrolamellar hepatocellular carcinoma: multiphasic CT features of the primary tumor on pre-therapy CT and pattern of distant metastases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Central stellate scar with internal calcification is a useful imaging feature that can help in the diagnosis of FLHCC."
    explanation: The series' own statement that this combination is diagnostically useful.
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A central stellate scar is present in approximately 65%-70% of cases, and calcifications - often located within this scar - are observed in 40%-68% of patients."
    explanation: >-
      A second, wider set of figures for the same two features. Curated
      alongside the CT series rather than merged with it - 65-70% and 73% are
      different populations, not a disagreement to average away.

- name: CK7 and CD68 Immunohistochemistry
  description: >-
    Co-expression of cytokeratin 7 and CD68 on the tumour cells, which with
    compatible morphology is treated as diagnostic. Neither marker alone is
    specific; the pair is the useful test, and CD68 is what separates this
    tumour from its closest histologic mimic.
  evidence:
  - reference: PMID:26712049
    reference_title: "Fibrolamellar carcinoma versus scirrhous hepatocellular carcinoma : diagnostic usefulness of CD68."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemically, all cases were positive for CK7 and for CD68 (n=4)."
    explanation: The staining result in every case of the series, for both markers.
  - reference: PMID:26712049
    reference_title: "Fibrolamellar carcinoma versus scirrhous hepatocellular carcinoma : diagnostic usefulness of CD68."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD68 immunostaining is a sensitive marker for FL-HCC that may be of use in routine diagnostic surgical pathology. Lack of CD68 staining should suggest caution in making a diagnosis of FL-HCC."
    explanation: >-
      States the test's sensitivity claim and, importantly, how a negative
      result should be read.
  - reference: PMID:35803261
    reference_title: "Human liver organoids for disease modeling of fibrolamellar carcinoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "when used in conjunction, along with compatible morphology, co-expression of CK7 and CD68 is diagnostic of FLC"
    explanation: >-
      States the conjunction requirement explicitly - it is the co-expression
      plus morphology that is diagnostic, not either stain on its own.
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FLHCC is distinguished by consistent positivity for cytokeratin 7 and epithelial membrane antigen, suggesting a dual lineage with features of both hepatocytes and cholangiocytes"
    explanation: >-
      Adds the interpretation the CK7 result carries - a dual hepatocyte and
      cholangiocyte lineage signature rather than a simple hepatocellular one.

differential_diagnoses:
- name: Scirrhous Hepatocellular Carcinoma
  description: >-
    The closest histologic mimic, sharing a fibrous stroma. PRKACA
    rearrangement testing separates them cleanly.
  evidence:
  - reference: PMID:25698061
    reference_title: "DNAJB1-PRKACA is specific for fibrolamellar carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas, which can closely mimic fibrolamellar carcinoma."
    explanation: Names the mimic and the assay used to distinguish it.

- name: Conventional Hepatocellular Carcinoma
  description: >-
    Distinguished by patient age, absent cirrhosis and risk factors, normal
    alpha-fetoprotein, and a genomic landscape that whole-genome sequencing
    shows to be different.
  evidence:
  - reference: PMID:25605237
    reference_title: "The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations, altered pathways and structural variants that characterized fibrolamellar hepatocellular carcinoma were distinct from those in hepatocellular carcinoma, further defining it as a distinct carcinoma."
    explanation: >-
      The genomic argument that this is a separate entity rather than an HCC
      variant - the basis for curating it as its own entry.

- name: Focal Nodular Hyperplasia
  description: >-
    The benign lesion this tumour is most often mistaken for on imaging,
    because both carry a central scar. The error matters in a specific
    direction: patients under surveillance for a presumed focal nodular
    hyperplasia have presented later with advanced fibrolamellar carcinoma. The
    scar's T2 signal and the presence of calcification are what separate them.
  evidence:
  - reference: PMID:32397993
    reference_title: "Clinical features and surgical outcomes of fibrolamellar hepatocellular carcinoma: retrospective analysis of a single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to some radiomorphological similarities with focal nodular hyperplasia (FNH) (both may present with a stellate central scar), FL-HCC can be misinterpreted as FNH"
    explanation: Names the shared feature and states the direction of the misdiagnosis.
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fibrous stroma within the tumor, particularly the central scar, is hypointense on both T1- and T2-weighted images - unlike in focal nodular hyperplasia, where the scar is usually hyperintense on T2."
    explanation: >-
      The MRI feature that discriminates them: the scar is T2-hypointense here
      and T2-hyperintense in focal nodular hyperplasia.

genetic:
- name: DNAJB1-PRKACA
  gene_term:
    preferred_term: PRKACA
    term:
      id: hgnc:9380
      label: PRKACA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  frequency: present in essentially all fibrolamellar carcinomas; 15/15 in the founding series
  notes: >-
    Curated as a structural fusion rather than a sequence variant. `gene_term`
    carries PRKACA because the slot is single-valued and the catalytic activity
    resides there; DNAJB1 (hgnc:5270) contributes the amino-terminal
    chaperone-binding domain and is bound on the pathophysiology node.
  evidence:
  - reference: PMID:24578576
    reference_title: "Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the FL-HCCs examined (15/15) suggests that this genetic alteration contributes to tumor pathogenesis."
    explanation: The founding recurrence figure.
  - reference: PMID:25605237
    reference_title: "The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lack of a second-hit mutation in the genomic landscape of fibrolamellar hepatocellular carcinoma makes the DNAJB1-PRKACA fusion protein the best target for diagnostic and therapeutic advancements."
    explanation: >-
      Establishes the absence of a recurrent cooperating lesion, which is why
      this entry treats the fusion as the driver rather than one of several.

treatments:
- name: Surgical Resection
  description: >-
    Hepatectomy is the mainstay and the only modality with a demonstrated
    survival effect in population data. Patients not treated surgically had
    roughly three times the risk of death.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Hepatectomy
    term:
      id: NCIT:C15249
      label: Hepatectomy
  target_mechanisms:
  - target: Hepatic Mass in a Non-Cirrhotic Liver
    description: >-
      Resection removes the tumour bulk; because the background liver is not
      cirrhotic, more of it can be taken than in conventional hepatocellular
      carcinoma.
  evidence:
  - reference: PMID:32052215
    reference_title: "Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients who were not treated with surgical intervention had about 3 times increased risk for death (HR 2.8, 95% CI 1.68-4.72, P = 0.000)."
    explanation: The population-based effect estimate this treatment rests on.

- name: Cytotoxic Chemotherapy
  description: >-
    Curated as a treatment that does not work. Chemotherapy is given to nearly
    half of patients in population data yet has no measurable effect on
    outcome, and the tumours were described as poorly chemoresponsive from the
    founding report onward. Recording the negative result is the point.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:32052215
    reference_title: "Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiation and chemotherapy did not significantly affect outcomes."
    explanation: >-
      Graded REFUTE because it contradicts the claim that this treatment
      benefits patients. The same sentence covers radiation.
  - reference: PMID:39326063
    reference_title: "DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are no standard treatments for advanced FLC, and clinical trials with targeted, conventional, and immune therapies have shown limited benefit."
    explanation: >-
      Supports the description's claim that no systemic option is established,
      across drug classes rather than only cytotoxics.

- name: DNAJB1-PRKACA Fusion-Neoantigen Peptide Vaccine with Nivolumab and Ipilimumab
  description: >-
    A synthetic long peptide spanning the fusion breakpoint, given with a
    poly-ICLC adjuvant and dual checkpoint blockade. This is the therapeutic
    payoff of the entry's single-driver framing: because the breakpoint falls
    inside an intron, the chimeric junction sequence is the same in every
    patient, so one off-the-shelf peptide is a shared neoantigen for the whole
    disease. Phase 1 only - the disease control figure comes from 12 evaluable
    patients and is not an efficacy result.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: Vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
    therapeutic_agent:
    - preferred_term: nivolumab
      term:
        id: NCIT:C68814
        label: Nivolumab
    - preferred_term: ipilimumab
      term:
        id: NCIT:C2654
        label: Ipilimumab
  target_mechanisms:
  - target: Chimeric DNAJ-PKAc Kinase Expression
    description: >-
      The immunogen is the chimeric junction itself, so the treatment targets
      the driver lesion directly rather than a downstream consequence of it.
  evidence:
  - reference: PMID:41286513
    reference_title: "A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fusion breakpoint occurs within an intron, making the sequence of the chimera consistent across patients. This allows a single vaccine to be broadly applicable for patients with FLC."
    explanation: >-
      States why a single shared peptide works for this disease - the intronic
      breakpoint makes the chimera's sequence identical across patients.
  - reference: PMID:41286513
    reference_title: "A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAJ-PKAc-specific T cell responses were detected in 9 of 12 patients after treatment."
    explanation: The immunological primary endpoint, which is what a phase 1 trial is powered for.
  - reference: PMID:41286513
    reference_title: "A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the subset of patients who completed the initial priming phase the disease control rate was 75% (9/12), with three partial responses (25%)."
    explanation: >-
      The clinical signal, quoted with its own denominator. Curated as an
      early-phase observation, not as an efficacy claim.
  - reference: PMID:41286513
    reference_title: "A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Grade 3 treatment-related adverse events were reported by six patients (37.5%)."
    explanation: The toxicity result, recorded alongside the response figures rather than omitted.

- name: Liver Transplantation
  description: >-
    Considered for liver-confined disease that cannot be resected. Reported
    five-year survival spans a wide range across series, and the individual
    reports make clear that nodal and vascular involvement drive the outcome
    rather than the transplant itself.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: Hepatic Mass in a Non-Cirrhotic Liver
    description: >-
      Total hepatectomy with grafting removes tumour that partial resection
      cannot clear, at the cost of lifelong immunosuppression.
  evidence:
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A systematic review of 35 series involving 575 patients indicated a 5-year survival rate ranging from 29% to 55% for those undergoing liver transplantation"
    explanation: >-
      The pooled survival range across 35 series. Quoted as a range rather than
      a point estimate because that is how the source reports it.
  - reference: PMID:29633928
    reference_title: "Living-Donor Liver Transplant for Fibrolamellar Hepatocellular Carcinoma With Hilar Lymph Node Metastasis: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our patient, with poor prognostic criteria such as hilar lymph node metastasis, microvascular invasion, and poor differentiation, had 22 months of tumor-free survival and 26 months of overall survival after having undergone living-donor liver transplant."
    explanation: >-
      A single case, curated for what it shows about the limits of the
      procedure: hilar nodal metastasis and microvascular invasion were present
      and the patient died at 26 months. One case is weak evidence and is
      recorded as such.

- name: Regional Lymph Node Sampling
  description: >-
    Curated because the evidence points two ways and both directions matter.
    Fibrolamellar histology independently predicts node positivity, so sampling
    is informative for staging; but in the same cohort, sampling itself carried
    no independent survival benefit. This entry records the staging rationale
    and the absent survival effect as separate evidence items rather than
    resolving them into a recommendation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Lymphadenectomy
    term:
      id: NCIT:C15275
      label: Lymphadenectomy
  evidence:
  - reference: PMID:35398630
    reference_title: "Prognostic Role of Lymph Node Sampling in Adolescent and Young Adults With Fibrolamellar Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FLC was an independent risk factor for LN positivity, suggesting a role for routine LN sampling in these patients."
    explanation: >-
      The staging rationale: this histology is itself a predictor of positive
      nodes, which is the study's argument for sampling.
  - reference: PMID:35398630
    reference_title: "Prognostic Role of Lymph Node Sampling in Adolescent and Young Adults With Fibrolamellar Carcinoma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In AYA patients with HCC, LN sampling was not associated with an independent survival benefit."
    explanation: >-
      Graded REFUTE against a survival-benefit claim, which the deep-research
      report asserted and this cohort does not support. The same paper supplies
      both items because it makes both findings.

- name: Aurora Kinase A Inhibition
  description: >-
    ENMD-2076, an oral Aurora A inhibitor, was the first drug taken into a
    trial on the strength of this entry's own mechanism - AURKA overexpression
    downstream of the fusion. It is curated because it did not work. A single
    partial response in 35 patients is the counterexample to reading a
    phosphoproteomic node as a validated drug target.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: AURKA-GSK3 Sub-Network Activation
    description: >-
      The drug targets Aurora kinase A, which is the node's own gene product.
  evidence:
  - reference: PMID:32154962
    reference_title: "Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent."
    explanation: >-
      Graded REFUTE against the claim that this treatment benefits patients.
      The response and stable-disease figures are quoted with the trial's own
      conclusion attached to them.
  - reference: PMID:32154962
    reference_title: "Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The study provided no rationale for further studying ENMD-2076 as a single agent in FLC."
    explanation: The trial's formal conclusion, quoted separately from the numbers behind it.

clinical_trials:
- name: NCT04248569
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Pilot trial of the DNAJB1-PRKACA fusion kinase peptide vaccine with
    nivolumab and ipilimumab in unresectable or metastatic disease. Published
    as a phase 1 report in 2025.
  evidence:
  - reference: clinicaltrials:NCT04248569
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The primary objective of the trial is the safety and tolerability of administering a vaccine targeting the DNAJB1-PRKACA fusion kinase, in combination with nivolumab and ipilimumab in patients with unresectable or metastatic FLC and with non-FLC solid tumors and to assess the T-cell response."
    explanation: >-
      The registry record establishing the trial's design and endpoints. Graded
      OTHER because a registration document is not itself study evidence; the
      results are curated on the treatment from PMID:41286513.

- name: NCT02234986
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Multicentre open-label phase 2 of oral ENMD-2076 in advanced disease.
    Completed and published - one partial response in 35 patients, and the
    investigators concluded against further single-agent development.
  evidence:
  - reference: clinicaltrials:NCT02234986
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The purpose of the study is to determine whether once-daily dosing with ENMD-2076 will be a safe and effective treatment in patients with FLC. Safety will be measured by looking at the adverse events that may happen and the efficacy will look at the progression of the disease over time."
    explanation: >-
      The registry record for the trial whose published results are curated on
      the Aurora Kinase A Inhibition treatment.

- name: NCT04380545
  phase: PHASE_II
  status: RECRUITING
  description: >-
    Phase I/II of nivolumab with fluorouracil and interferon alfa-2b in
    unresectable disease.
  evidence:
  - reference: clinicaltrials:NCT04380545
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This phase I/II trial studies the side effects and how well nivolumab, fluorouracil, and interferon alpha 2b work for the treatment of fibrolamellar cancer (liver cell cancer) that cannot be removed by surgery (unresectable)."
    explanation: >-
      The registry record. No results are published, so nothing is curated as a
      treatment on the strength of it.

- name: NCT06620302
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Phase I with a phase II feasibility cohort for fibrolamellar carcinoma,
    testing the Bcl-xL degrader DT2216 with irinotecan in relapsed or
    refractory paediatric and young-adult solid tumours.
  evidence:
  - reference: clinicaltrials:NCT06620302
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This phase I/II trial tests the safety, side effects and best dose of DT2216 in combination with irinotecan and how well it works in treating children, adolescents and young adults with solid tumors and fibrolamellar cancer that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory)."
    explanation: >-
      The registry record. Listed because the disease has a named feasibility
      cohort in it, not because any result is available.

biochemical:
- name: Serum unsaturated vitamin B12 binding capacity
  presence: INCREASED
  context: >-
    The classic serum marker of this tumour, and the historical counterpart to
    the normal alpha-fetoprotein: in the founding 1982 series every patient
    with a raised value had a normal alpha-fetoprotein and no cirrhosis. It is
    a correlation established in a small cohort and has not displaced imaging
    or fusion testing in practice, so it is curated as a supporting laboratory
    finding rather than a diagnostic test.
  evidence:
  - reference: PMID:6288165
    reference_title: "High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven of the 10 patients had fibrolamellar hepatocellular carcinoma, a recently recognised histological variant, which was found in only one young patient without increased serum unsaturated vitamin B12 binding capacity and no alpha-fetoprotein among the remaining 97."
    explanation: >-
      The enrichment result: seven of ten patients with a raised value had this
      histology, against one case among the other 97 patients.
  - reference: PMID:6288165
    reference_title: "High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This high degree of correlation between increased serum unsaturated vitamin B12 binding capacity and fibrolamellar hepatocellular carcinoma has not been reported before."
    explanation: >-
      The authors' own framing of the finding as a correlation, which is the
      strength this entry claims for it.

prevalence:
- population: United States, SEER 2000-2016
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.02
  rate_denominator: POPULATION_PER_YEAR
  notes: Age-adjusted incidence from 300 SEER-registered cases.
  evidence:
  - reference: PMID:32052215
    reference_title: "Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall age-adjusted incidence of FLC between 2000 and 2016 was 0.02 per 100,000 per year."
    explanation: The population-based incidence figure this record normalizes.

epidemiology:
- name: Young Age at Diagnosis
  description: >-
    Median age at diagnosis is 27, decades below conventional hepatocellular
    carcinoma. The SEER distribution is bimodal, with a second peak in the
    eighth decade that is less often emphasised in the clinical literature.
  evidence:
  - reference: PMID:32052215
    reference_title: "Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at diagnosis was 27 ± 22 years."
    explanation: The median age this record reports.
  - reference: PMID:32052215
    reference_title: "Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A bimodal distribution was observed where the highest incidences occurred between 15-19 years and 70-74 years."
    explanation: >-
      The bimodality, which the "adolescents and young adults" framing common
      elsewhere in the literature omits.

progression:
- phase: Population-Based Survival
  notes: >-
    SEER cause-specific survival is 72.0% at one year and 32.9% at five, with a
    median of 32.9 months - roughly three times the 11.7-month median for
    conventional hepatocellular carcinoma in the same analysis.
  evidence:
  - reference: PMID:32052215
    reference_title: "Fibrolamellar Hepatocellular Carcinoma: A Population-Based Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One- and 5-year cause-specific survival for FLC was 72.0% and 32.9%, respectively, with a median survival of 32.9 months."
    explanation: The all-stage survival figures this phase records.

- phase: Advanced Disease
  notes: >-
    Five-year overall survival is under 10% once disease is advanced. This is
    not in conflict with the SEER figure above: that one is all-stage and
    cause-specific, this one is restricted to advanced disease. The two are
    recorded separately rather than reconciled.
  evidence:
  - reference: PMID:39326063
    reference_title: "DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Outcomes are poor for advanced disease, with a 5-year overall survival of less than 10%"
    explanation: The advanced-disease survival figure, whose population differs from the SEER record above.

- phase: Recurrence After Resection
  notes: >-
    Recurrence after a curative-intent resection is the rule rather than the
    exception, and re-resecting it is worth doing. The reported recurrence
    fraction ranges from most of a small single-centre series to all patients
    in a pooled relapse review, so the entry records the sources separately
    rather than settling on one number. Reported survival after re-resection is
    substantially longer than without, which is why an aggressive surgical
    posture persists at relapse.
  evidence:
  - reference: PMID:32397993
    reference_title: "Clinical features and surgical outcomes of fibrolamellar hepatocellular carcinoma: retrospective analysis of a single-center experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection."
    explanation: >-
      A single-centre surgical series: five of eight patients recurred at a
      median of nine months, and a quarter went on to a second resection.
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "found that all patients experienced recurrence after initial surgery, with a median time to recurrence of 2.2 years. For those who underwent re-resection, the median OS increased to 4.7 years, with a 5-year survival rate of 48%."
    explanation: >-
      A pooled relapse review reporting universal recurrence and the survival
      gain from re-resection. Kept separate from the single-centre figures
      above rather than averaged with them.
  - reference: PMID:41178855
    reference_title: "Fibrolamellar hepatocellular carcinoma: Advances, challenges and opportunities in a rare malignancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case series have demonstrated that re-resection of recurrent FLHCC lesions can lead to improved survival outcomes, with median OS extending up to 122 months in some cases"
    explanation: >-
      The upper end of the reported re-resection survival, quoted with the
      source's own hedge that it is what case series have shown in some cases.

animal_models:
- name: CRISPR/Cas9 Dnajb1-Prkaca fusion mouse
  species: Mouse
  genotype: Dnajb1-Prkaca fusion engineered by CRISPR/Cas9 deletion of the syntenic chromosome 8 region
  description: >-
    CRISPR/Cas9 vectors delivered by hydrodynamic tail vein injection to adult
    FVB/N mouse liver, juxtaposing Dnajb1 exon 1 with Prkaca exon 2. The mice
    carried no other engineered alteration and were exposed to no liver toxin
    or carcinogen, which is what makes this a sufficiency experiment rather
    than a cooperation one.
  publication: PMID:28923495
  modeled_mechanisms:
  - target: Hepatocyte Transformation and Clonal Proliferation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      The fusion alone produced neoplasms in 12 of 15 mice and none of 11
      controls, with histologic and cytologic features of human tumours.
    limitations: >-
      Tumours are described as indolent in the companion model, and the
      14-month latency is long relative to the human disease course, so the
      model reproduces initiation better than it reproduces tempo.
    evidence:
    - reference: PMID:28923495
      reference_title: "CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Livers from 12 of the 15 mice given the vectors to induce the Dnajb1-Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms."
      explanation: The controlled result establishing this model as informative for the transformation node.

- name: Transposon-mediated DNAJB1-PRKACA mouse with beta-catenin activation
  species: Mouse
  genotype: DNAJB1-PRKACA chimeric cDNA or endogenous fusion, with and without activated beta-catenin
  description: >-
    CRISPR-Cas9 plus transposon-mediated somatic gene transfer, used both to
    show the fusion drives tumours and to test cooperation with beta-catenin
    and with hepatotoxin-induced injury.
  publication: PMID:29162699
  modeled_mechanisms:
  - target: Wnt/beta-Catenin Cooperation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Genetic beta-catenin activation significantly enhanced fusion-driven
      tumorigenesis.
    limitations: >-
      Cooperation is demonstrated in mouse; in humans the support is recurrent
      Wnt pathway mutations, which is an association rather than a
      demonstration, so the human claim is weaker than the mouse one.
    evidence:
    - reference: PMID:29162699
      reference_title: "DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Tumorigenesis was significantly enhanced by genetic activation of β-catenin"
      explanation: The cooperation result this link records.

- name: zfDnaJa-Pkaca hepatocyte-expressing zebrafish
  species: Zebrafish
  genotype: hepatocyte-restricted ectopic expression of zebrafish Dnaja-Pkaca
  description: >-
    A larval zebrafish model expressing the zebrafish orthologue of the fusion
    in hepatocytes. Its point is live imaging of the earliest events, which the
    mouse models cannot show: the innate immune infiltrate appears before any
    tumour does.
  publication: PMID:32102783
  modeled_mechanisms:
  - target: Hepatocyte Transformation and Clonal Proliferation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Fusion expression enlarges the liver and the hepatocytes in it, with an
      early neutrophil and macrophage infiltrate.
    limitations: >-
      A zebrafish orthologue of the fusion in larval liver is not the human
      chimera in an adult human liver, and the readout is hepatomegaly and
      inflammation rather than a lamellar-stroma tumour. It reports early
      events, not the disease.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The construct is zebrafish Dnaja-Pkaca, not human DNAJB1-PRKACA, so the
        chimeric junction sequence that defines the human lesion - and that the
        peptide vaccine targets - is not the sequence expressed here.
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The measured quantities are liver size, hepatocyte size and immune-cell
        infiltration in a larva. The node's quantity is transformation of
        hepatocytes into a tumour with lamellar stroma and eosinophilic
        polygonal cytology, neither of which this model reports.
    evidence:
    - reference: PMID:32102783
      reference_title: "DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Expression of zfDnaJa-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size."
      explanation: The growth phenotype that ties this model to the transformation node.
    - reference: PMID:32102783
      reference_title: "DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of fibrolamellar carcinoma."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "FLC larvae exhibit early innate immune inflammation characterized by early infiltration of neutrophils and macrophages into the liver microenvironment."
      explanation: >-
        The early inflammatory finding this model exists to show, which is not
        otherwise represented in this entry's pathograph.

experimental_models:
- name: Patient-derived fibrolamellar carcinoma organoids
  experimental_model_type: ORGANOID
  description: >-
    Twenty-one organoid lines grown from nine patients - primary tumour,
    metastases, and matched non-tumour liver from the same operations. The
    matched normal lines are what make this a comparison rather than a culture
    collection, and the panel was taken through a drug screen.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:35803261
  modeled_mechanisms:
  - target: Hepatocyte Transformation and Clonal Proliferation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The organoids reproduce the histology, immunohistochemistry and
      transcriptome of the tumours they came from.
    limitations: >-
      An organoid has no stroma, so nothing about the lamellar fibrous bands -
      the feature the disease is named for - can be studied in it. Seven of the
      nine donors had received chemotherapy before resection, so the lines are
      not uniformly treatment-naive.
    evidence:
    - reference: PMID:35803261
      reference_title: "Human liver organoids for disease modeling of fibrolamellar carcinoma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor."
      explanation: The fidelity claim, across three independent kinds of comparison.
    - reference: PMID:35803261
      reference_title: "Human liver organoids for disease modeling of fibrolamellar carcinoma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver."
      explanation: >-
        The composition of the panel, including the matched non-tumour lines
        that give the comparison its control.
- name: AML12 DNAJ-PKAc gene-edited hepatocyte line
  experimental_model_type: CELL_LINE
  description: >-
    Mouse hepatocytes gene-edited to express DNAJ-PKAc, used for the
    phosphoproteomics and drug screening that defined the Hsp70/AKAP-Lbc
    scaffolding mechanism.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:31063128
  modeled_mechanisms:
  - target: Acquired Hsp70 Scaffolding Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      The line reproduces the fusion's Hsp70 recruitment and ERK-biased
      signalling, and its proliferation is selectively blocked by Hsp70 plus
      MEK inhibitor combinations.
    limitations: >-
      A mouse hepatocyte line reports the signalling consequences of the fusion
      but not the tissue architecture, stroma or clinical course; nothing about
      the lamellar fibrosis can be learned from it.
    evidence:
    - reference: PMID:31063128
      reference_title: "An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Drug screening reveals Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12DNAJ-PKAc cells."
      explanation: >-
        Selective dependence on the scaffolding partners establishes the line
        as informative for this node.

discussions:
- discussion_id: flc_lamellar_stroma_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    How does a hepatocyte carrying the DNAJB1-PRKACA fusion induce the parallel
    lamellar collagen bands the disease is named for?
  rationale: >-
    The lamellar stroma is the tumour's defining histologic feature and the
    origin of its name, yet the entry cannot connect it to the driver. TGF-beta
    overexpression is the proposed route in the literature, but the support is
    correlative and histological rather than a demonstrated causal chain, so
    the edge from transformation to stroma is curated with unknown
    intermediates and no evidence attached. The gap matters because the
    fibrosis is not cirrhotic and the surrounding liver is normal, so whatever
    drives it is tumour-directed rather than a background process.
  attaches_to:
  - pathophysiology#Hepatocyte Transformation and Clonal Proliferation
  - pathophysiology#Lamellar Fibrous Stroma Formation

- discussion_id: flc_who5_versus_mondo_placement
  kind: INTERPRETATION
  prompt: >-
    Is fibrolamellar carcinoma a subtype of hepatocellular carcinoma or a
    separate entity, and what should the entry assert?
  rationale: >-
    MONDO places MONDO:0006210 under hepatocellular carcinoma, and this entry's
    `parents` follows it. The evidence curated here points the other way: the
    genomic landscape is distinct, the driver is absent from conventional
    hepatocellular carcinoma and from every other liver tumour tested, the
    patient population and risk-factor profile do not overlap, and the
    published sequencing describes it as "a distinct carcinoma". The entry does
    not attempt to resolve the ontology question - it uses MONDO's term and
    hierarchy as given, curates the evidence that bears on the placement, and
    records the disagreement here rather than silently asserting either answer.
  attaches_to:
  - disease#Fibrolamellar Hepatocellular Carcinoma
  - differential_diagnoses#Conventional Hepatocellular Carcinoma

notes: >-
  Promotion from a subtype row. Before this entry, fibrolamellar carcinoma
  existed in the knowledge base only as a `has_subtypes` row on
  `Hepatocellular_Carcinoma`. It is promoted here under the cancer granularity
  ladder (design decisions 3a): it has its own MONDO term, its own driver
  lesion, a distinct patient population, and a distinct treatment pathway. The
  pointer row is deliberately left in place on the parent rather than deleted,
  so a reader arriving at the hepatocellular carcinoma entry is still told the
  variant exists and where it went.

  Ontology placement is contested and not resolved here. See the
  `flc_who5_versus_mondo_placement` discussion. `parents` follows MONDO.

  Two survival figures that describe different populations. SEER gives 32.9%
  five-year cause-specific survival across all stages; a 2024 review gives
  under 10% five-year overall survival in advanced disease. These are not in
  conflict and are not averaged - they are curated as separate `progression`
  phases with their populations stated.

  A phenotype and a treatment are curated as negative findings. Normal
  alpha-fetoprotein is bound to the HP term for *elevated* AFP with
  `supports: REFUTE`, because the discriminating observation in this disease is
  that the value is normal. Cytotoxic chemotherapy carries a REFUTE item
  because population data show no effect on outcome despite widespread use.
  Both are recorded as negatives rather than omitted.

  The fusion is near-universal in this tumour but not unique to it. The
  specificity result curated on `DNAJB1-PRKACA Fusion Detection` was obtained
  across liver tumours, and it holds there. A later series found the same
  fusion in oncocytic pancreatic and biliary neoplasms, so the test is not
  site-agnostic. Both results are curated on that diagnosis entry, as a SUPPORT
  and a REFUTE item, rather than one being softened to accommodate the other.

  Not curated. The research report describes neurotensin as a candidate
  biomarker, single-cell work on rewired SPP1-CD44 and MIF-ACKR3 signalling,
  snATAC-seq super-enhancer landscapes, and in vitro drug screens nominating
  HDAC and topoisomerase inhibitors and napabucasin. All trace to preprints or
  sources this session did not fetch, so none is included. The report also
  offered `NCIT:C158`, which does not exist, and `GO:0016575`, which is
  obsolete; neither is bound.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Fibrolamellar Hepatocellular Carcinoma · 2026-09-07T01:41:02Z · View source

De-novo creation of kb/disorders/Fibrolamellar_Hepatocellular_Carcinoma.yaml for MONDO:0006210, promoting the disease from a five-line has_subtypes row on Hepatocellular_Carcinoma to its own entry. Claimed via issue #11279. DEEP RESEARCH AND THE PROVIDER FALLBACK No provider was named, so the skill default is falcon. No EDISON_API_KEY is configured in this environment. Rather than hand-substituting a provider and explaining it in prose here -- which the skill explicitly warns against, since six committed records already do that and the substitution is invisible to every query -- the run used `just dr_fallback='--fallback' research-disorder falcon`. The report records the substitution itself: fell_back: true, requested_provider: falcon, and a provider_attempts entry with ProviderNotConfiguredError. It fell through to claude_code (19 web searches, 21 turns, 35 citations, 287s) and the file was renamed to -claude_code on completion. Both validation sections were retro-fitted. References: 35/35 resolved, 0 unresolved, 0 off topic, 1/1 quoted claim verified. Terms: three flagged and none bound -- NCIT:C158 does not exist, GO:0016575 is obsolete (the same obsolete term the BPDCN report offered in the previous session, which suggests the template elicits it), and HP:0033834 is Malaise rather than the "Fatigue-related" the report called it. WHY THIS DISEASE EARNED ITS OWN ENTRY The promotion argument is the entry's spine and is evidenced rather than asserted. Whole-genome sequencing of ten tumours found the mutations, pathways and structural variants distinct from hepatocellular carcinoma and concluded it is "a distinct carcinoma". The driver is absent from 25 conventional HCCs, 25 cholangiocarcinomas, 25 adenomas and 5 hepatoblastomas tested alongside it. The patient population does not overlap. And the treatment path diverges: surgery is the only modality with a measurable effect. THE CAUSAL CHAIN 13 nodes, no orphans. A ~400 kb chromosome 19 deletion fuses DNAJB1 to PRKACA; the chimera is expressed ~10-fold over wild-type PRKACA and raises cAMP-stimulated PKA activity with unchanged Km, so the excess is abundance rather than altered catalysis. From there the chain forks into four evidenced arms -- an acquired Hsp70/AKAP-Lbc scaffolding function feeding ERK-biased MAPK signalling, SIK inactivation releasing CRTC2-p300 transcription, an AURKA/GSK3 route to MYC protein, and Wnt/beta-catenin cooperation -- converging on hepatocyte transformation. The node that carries the most weight is the neomorphic claim. Overexpressing wild-type PRKACA does not reproduce the fusion's oncogenic activity, and the fusion recruits Hsp70, which wild-type PKA cannot. Together those make this a structurally novel kinase rather than simply more PKA, and the entry says so on the evidence rather than by assertion. A separate arm reaches hyperammonemic encephalopathy: raised AURKA and c-MYC drive ornithine decarboxylase up and ornithine transcarbamylase down, so the tumour phenocopies a urea cycle disorder in a patient whose non-tumour liver is working. The source frames the c-Myc-to-ODC step as a proposal, and the edge evidence quotes it as a proposal rather than upgrading it. TWO NEGATIVE FINDINGS CURATED AS NEGATIVES - Normal alpha-fetoprotein is bound to HP:0006254, which names *elevated* AFP, with supports: REFUTE. The discriminating observation in this disease is that the value is normal; grading the evidence REFUTE against the term records that, where omitting the phenotype would lose it and grading it SUPPORT would invert it. - Cytotoxic chemotherapy carries a REFUTE item. It is given to roughly half of SEER patients and does not affect outcome. A treatment that does not work is worth curating as such. JUDGMENT CALLS - The parent's has_subtypes row was kept, not deleted, and rewritten to point at the new entry. Deleting it would assert the WHO-5 separation more strongly but leaves a reader at Hepatocellular_Carcinoma with no signal that the entity exists. - `parents` follows MONDO (hepatocellular carcinoma) even though the curated evidence argues for separation. The disagreement is recorded as an INTERPRETATION discussion rather than resolved unilaterally: this entry should not silently re-parent a MONDO term. - Two survival figures are kept apart. SEER gives 32.9% five-year cause-specific across all stages; a 2024 review gives under 10% five-year overall in advanced disease. Different populations, different endpoints; curated as separate progression phases with the populations stated. - The lamellar stroma -- the feature the disease is named for -- is curated with an INDIRECT_UNKNOWN_INTERMEDIATES edge and no evidence, because the TGF-beta route in the literature is correlative. A KNOWLEDGE_GAP records this rather than the edge implying more than is known. GENEREVIEWS Searched and absent (0 PubMed hits), as expected for a somatic neoplasm. VALIDATION - `just validate-disorders` over both changed files: passed, 40/40 snippets on the new entry. - `just validate`: schema, term and reference validation all passed. - entity-ref, causal-target, duplicate-key, enum-value and qualifier-term checks: all OK. 13 nodes, no orphans. - whole-KB title-snippet, snippet-grading, snippet-length, folded-hyphen and environmental gates: no new violations, no baseline touched. - `just compliance`: 74.6%. - All 12 reference_title values were derived programmatically from references_cache frontmatter, never typed.

Claude Code ▸
Fibrolamellar Hepatocellular Carcinoma (FLC/FL-HCC): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 56 citations 2026-09-07T01:00:59.157831

Fibrolamellar Hepatocellular Carcinoma (FLC/FL-HCC): Comprehensive Research Report

1. Disease Information

Overview. Fibrolamellar hepatocellular carcinoma (FLC, also FL-HCC or FLHCC) is a rare, histologically and molecularly distinct primary liver malignancy that predominantly arises in adolescents and young adults without underlying cirrhosis, viral hepatitis, or other chronic liver disease — a striking contrast to conventional hepatocellular carcinoma (HCC), which is overwhelmingly a cirrhosis-associated cancer of older adults. FLC is defined pathologically by large polygonal eosinophilic tumor cells embedded in parallel lamellae of collagenous stroma, and molecularly by a near-universal somatic DNAJB1-PRKACA gene fusion arising from a ~400 kb heterozygous deletion on chromosome 19p13.12 (Medscape; PMC8448801; PMC10787162).

Key identifiers: - MONDO: MONDO:0006210 - Orphanet: ORPHA:401920 (also cross-referenced under ORPHA:33402, Pediatric hepatocellular carcinoma) (Orphanet) - ICD-O-3: 8171/3 (fibrolamellar carcinoma morphology code) - ICD-10: C22.0 (liver cell carcinoma, as a subtype) - MeSH: D049688 (Carcinoma, Hepatocellular is D006528; fibrolamellar variant indexed under related HCC headings)

Synonyms: Fibrolamellar carcinoma; fibrolamellar hepatocellular carcinoma; fibrolamellar liver cancer; polygonal cell type hepatocellular carcinoma with fibrous stroma (older WHO terminology).

Information source. Most quantitative data below derive from aggregated disease-level resources — the SEER registry, the National Cancer Database (NCDB), and pooled case-series/systematic reviews — supplemented by individual case reports for rare presentations (e.g., paraneoplastic syndromes). Because FLC is rare, single-institution and multi-institution retrospective cohorts (rather than prospective trials) are the dominant human evidence base.

2. Etiology

Disease Causal Factors

The molecular driver of FLC is a somatic ~400 kb heterozygous deletion on chromosome 19p13.12 that fuses the first exon of DNAJB1 (encoding a heat-shock protein 40/Hsp40 co-chaperone) in-frame to exons 2–10 of PRKACA (the catalytic alpha subunit of protein kinase A, PKA) (PubMed:29162699; PNAS:1716483114). This fusion is found in >80–100% of morphologically classic FLC cases across independent series and is considered the pathognomonic, essentially disease-defining lesion (PMC5758901).

There is no established environmental, infectious, or lifestyle cause. Unlike conventional HCC, FLC arises in the absence of viral hepatitis (HBV/HCV), alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease, hemochromatosis, or cirrhosis of any etiology (NORD; PMC9750232 "Fibrolamellar Hepatocellular Carcinoma in the Absence of Risk Factors").

Risk Factors

Genetic risk factors: - The defining lesion is somatic, not germline — occurring de novo in tumor tissue and not inherited or transmissible to offspring (Fibrolamellar Cancer Foundation). - Whole-genome sequencing of 10 patient tumor/normal pairs found FLC has a remarkably low somatic coding-mutation burden, among the lowest of any solid tumor sequenced, with the DNAJB1-PRKACA fusion as essentially the only recurrent structural event and no consistent "second hit" (PMC4359253/Oncotarget:2712). - A single case report describes a 14-year-old girl with FLC carrying both a germline and somatic TP53 mutation, raising the possibility that FLC could rarely fall within the Li-Fraumeni tumor spectrum, though this is not an established recurrent association (Familial Cancer, 10.1007/s10689-017-9998-5). - No confirmed susceptibility loci, modifier genes, or GWAS-defined risk alleles have been established for FLC given its rarity.

Environmental/demographic risk factors: - Age: Bimodal incidence peaks at 15–19 years and 70–74 years, but the disease is classically associated with adolescents and young adults (typical reported range 14–33 years), with rare cases from age 2 to 74 (npj Precision Oncology, 10.1038/s41698-023-00371-2). - Race/ethnicity: In the U.S., >85% of patients are non-Hispanic white, with smaller proportions among Chinese Americans (~6%), Black patients (~4%), and white Hispanic patients (~4%) — a markedly different demographic distribution than conventional HCC (PubMed:32052215). - Sex: No strong sex predominance is consistently reported across series (unlike conventional HCC's male predominance), though some cohorts report a slight male-favoring trend as a prognostic (not necessarily risk) factor. - No family history association has been established (sporadic disease).

Protective Factors

No genetic or environmental protective factors have been identified in the literature; this reflects both disease rarity and lack of dedicated case-control epidemiological studies.

Gene-Environment Interactions

None established. Given the essentially monogenic somatic driver (DNAJB1-PRKACA) and absence of implicated environmental exposures, there is no described gene-environment interaction model for FLC, unlike conventional HCC (where HBV/HCV × alcohol × metabolic risk interactions are well characterized).

3. Phenotypes

FLC's clinical phenotype is notable for vague, insidious presentation and, critically, absence of the stigmata of chronic liver disease seen in conventional HCC.

Phenotype Frequency Suggested HPO term
Abdominal pain ~72% (most common symptom) HP:0002027 (Abdominal pain)
Abdominal distension/fullness ~44% HP:0003270 (Abdominal distention)
Anorexia/weight loss ~32% HP:0002039 (Anorexia); HP:0001824 (Weight loss)
Hepatomegaly / palpable abdominal mass Common physical finding HP:0002240 (Hepatomegaly)
Malaise/constitutional symptoms Frequent HP:0033834 (Fatigue-related)
Fever Reported HP:0001945 (Fever)
Jaundice ~20% HP:0000952 (Jaundice)
Gynecomastia (males) Rare, due to tumor aromatase activity converting androgens to estrogens HP:0000771 (Gynecomastia)
Hyperammonemic encephalopathy (paraneoplastic) Rare but life-threatening complication HP:0001982 (Hyperammonemia); HP:0002480 (Encephalopathy)
Absence of portal hypertension/cirrhosis stigmata Characteristic negative finding —
Metastatic sites: lymph nodes, lung, peritoneum, bone, pancreas, ovary Variable, at diagnosis or recurrence —
Rare paraneoplastic: cold agglutinin disease, Budd-Chiari syndrome, recurrent DVT/PE, cardiac spread with IVC obstruction, hyperthyroidism Case-report level —

(Source: Chinese Clinical Oncology review, cco.amegroups.org/article/view/21275; PMC12576631; PMC6304646; PMC11002470)

Phenotype characteristics: - Onset: Typically adolescent/young adult onset, though the true age range spans 2–74 years with a secondary elderly peak in registry data. - Progression: Often insidious for months before diagnosis due to nonspecific symptoms; disease is frequently locally advanced or has nodal/metastatic spread at presentation because of this diagnostic delay. - Severity/frequency: Symptom severity is variable; a subset of patients are diagnosed incidentally. - Quality of life impact: Not systematically measured with validated instruments (EQ-5D/SF-36) in FLC-specific studies; QoL burden is inferred from the aggressive natural history, high recurrence rate, and the young age of patients (loss of years of life, fertility/oncofertility concerns, and psychosocial burden of a rare cancer diagnosis in adolescence).

Hyperammonemic Encephalopathy — Mechanistic Detail

This is a distinctive, often under-recognized FLC paraneoplastic phenotype: tumor cells show upregulation of glutaminase (GLS), which generates ammonia from glutamine, coupled with downregulation of ornithine transcarbamylase and glutamine synthetase (GS) — the ammonia-detoxifying enzymes. Net tumor ammoniagenesis overwhelms the (non-cirrhotic) residual liver's clearance capacity, producing severe hyperammonemic encephalopathy disproportionate to tumor burden or synthetic liver failure (PMC9922532; PMC4828114). Immunohistochemistry shows weak/diffuse GS expression in tumor cells.

4. Genetic/Molecular Information

Causal Gene Fusion

DNAJB1-PRKACA is the signature and essentially universal driver: - DNAJB1 (HGNC:14887; DnaJ heat shock protein family member B1) exon 1 fused in-frame to - PRKACA (HGNC:9380; protein kinase cAMP-activated catalytic subunit alpha) exons 2–10 - Resulting from a ~400 kb heterozygous deletion on chromosome 19p13.12 (PubMed:29162699). - The fusion transcript is expressed at ~10-fold higher levels than wild-type PRKACA, and confers elevated cAMP-stimulated PKA catalytic activity relative to normal liver (ScienceDirect:S2772572322001911). - Detected in 99–102/103 (99%) of morphologically classic FLC cases in the largest multicenter FISH validation series (PubMed:35777788), and by RT-PCR in 92% (24/26) of tested cases, with the fusion transcript essentially specific to FLC among primary liver tumors tested (though see the diagnostic caveat below) (PMC5758901).

Variant Classification and Functional Consequence

  • Somatic, not germline (essentially always) — arises in the tumor only.
  • Functional impact: Gain-of-function/neomorphic — the fusion is not merely PRKACA overexpression; ectopic overexpression of wild-type PRKACA alone fails to recapitulate FLC's oncogenic phenotype, indicating the DNAJB1 moiety confers a qualitatively distinct, "acquired scaffolding function" (PMC6533061) that (a) recruits Hsp70 into an altered PKA holoenzyme complex, and (b) via the upregulated scaffold protein AKAP-Lbc, clusters DNAJ-PKAc/Hsp70 with a RAF-MEK-ERK signaling module.
  • Structural biology studies of the PKA RIIβ holoenzyme containing the DNAJB1-PKAc fusion reveal protomer asymmetry and fusion-induced allosteric perturbations relative to wild-type PKA holoenzyme (PMC7793292).

Modifier/Cooperating Pathways

  • Wnt/β-catenin (CTNNB1) pathway: DNAJB1-PRKACA interacts with β-catenin, and tumorigenesis is significantly enhanced by concurrent β-catenin activation in mouse models; this is consistent with recurrent Wnt-pathway mutations observed in human FLC series (PubMed:29162699; PNAS:1716483114). (Note: dedicated large-cohort CTNNB1 mutation-frequency data were not retrievable in this search pass and should be verified against primary genomic-landscape papers before citing a specific percentage.)
  • SIK/CRTC2/p300 axis (2024 mechanistic advance): A 2024 Cancer Discovery study (10.1158/2159-8290.CD-24-0634) showed DNAJB1-PRKACA phosphorylates and inactivates salt-inducible kinases (SIKs), deregulating the CRTC2 transcriptional coactivator and p300 acetyltransferase, producing global histone hyperacetylation and transcriptional reprogramming that drives malignant growth — nominating CRTC2/p300 as a therapeutic target.
  • RAS/MAPK and AURKA/GSK3-MYC networks: Two downstream signaling branches have been mapped: (1) RAS/MAPK pathway components, and (2) an Aurora Kinase A (AURKA)/GSK3 sub-network with activity toward MYC — oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms (PMC9925115).
  • Oncogenic addiction: FLC tumor cells show dependency ("oncogenic addiction") specifically on the fusion kinase, supporting the fusion as the primary therapeutic vulnerability (PubMed:36302174).

Mutational Burden

Whole-genome sequencing of paired tumor/normal samples from 10 patients found relatively few coding somatic mutations — among the lowest mutation burdens described for any sequenced solid tumor — with no consistent recurrent "second-hit" mutation beyond the founding fusion event (PMC4359253).

Epigenetic Information

  • Single-nucleus multi-omic profiling (snATAC-seq + snRNA-seq, 2024–2025) has revealed cell-type-specific chromatin accessibility, transcription factor networks (notably CREB3L1), microRNA regulatory elements, and super-enhancers, including super-enhancers near FLC-enriched genes such as CDH11 and SLC16A14 (Nature Scientific Reports 10.1038/s41598-026-44899-2; bioRxiv 10.1101/2024.12.11.627911).
  • Global histone hyperacetylation downstream of CRTC2/p300 deregulation is a key epigenetic consequence of the fusion kinase (Cancer Discovery 2024).

Chromosomal Abnormalities

The defining lesion is itself the ~400 kb interstitial deletion at 19p13.12 producing the DNAJB1-PRKACA fusion; beyond this, FLC genomes are notably stable/quiet, without the widespread aneuploidy or chromothripsis seen in many other cancers (PMC4359253).

Diagnostic Caveat on Fusion Specificity

Although historically considered pathognomonic, DNAJB1-PRKACA fusions have also been reported in oncocytic pancreatic and biliary neoplasms, meaning the fusion is not absolutely exclusive to FLC and must be interpreted alongside morphology and clinical context (Modern Pathology 10.1038/s41379-019-0398-2).

Suggested ontology bindings: HGNC:9380 (PRKACA), HGNC:14887 (DNAJB1), HGNC:11986 (TP53, for the rare germline-mutation case), GO:0004691 (cAMP-dependent protein kinase activity), GO:0007190 (activation of adenylate cyclase activity), GO:0016575 (histone deacetylation, inverse direction relevant), NCIT for fusion gene concept.

5. Environmental Information

  • Environmental factors: None established. FLC is not associated with aflatoxin exposure, industrial toxins, or occupational carcinogens the way conventional HCC or angiosarcoma can be.
  • Lifestyle factors: No association with alcohol use, smoking, obesity/metabolic syndrome, or diet has been demonstrated; this is a key point of contrast with conventional HCC risk-factor profiles.
  • Infectious agents: No association with HBV, HCV, or other hepatotropic pathogens. This absence is itself diagnostically informative — FLC is essentially defined in part by exclusion of viral/infectious hepatocarcinogenesis (NORD; Liver Foundation Australia).

6. Mechanism / Pathophysiology

Ordered Causal Chain (Proposed Sequence)

  1. A somatic ~400 kb heterozygous deletion at chromosome 19p13.12 occurs in a hepatocyte (or hepatic progenitor/biliary-hepatocyte intermediate cell), fusing DNAJB1 exon 1 in-frame to PRKACA exons 2–10 — leads to formation of the chimeric DNAJB1-PRKACA transcript and protein (demonstrated; PubMed:29162699).
  2. The fusion transcript is overexpressed (~10-fold over wild-type PRKACA) — results in markedly elevated, and qualitatively altered, cAMP-stimulated PKA catalytic activity, because the DNAJB1 moiety confers Hsp70-recruiting scaffold properties absent from wild-type PKA (demonstrated in vitro/structural studies; PMC6533061, PMC7793292).
  3. The altered PKA holoenzyme, via upregulated AKAP-Lbc, clusters DNAJ-PKAc/Hsp70 subcomplexes with a RAF-MEK-ERK kinase module — leads to aberrant, spatially organized MAPK pathway activation (demonstrated; PMC6533061).
  4. In parallel, DNAJB1-PRKACA phosphorylates and inactivates salt-inducible kinases (SIKs) — results in deregulation of the CRTC2 coactivator and p300 acetyltransferase, driving global histone hyperacetylation and a pro-tumorigenic transcriptional program (demonstrated 2024; Cancer Discovery 10.1158/2159-8290.CD-24-0634).
  5. Downstream, an AURKA/GSK3 sub-network stabilizes MYC oncoprotein — leads to enhanced proliferative and cell-cycle-driving transcriptional output (demonstrated; PMC9925115).
  6. The fusion kinase also interacts directly with β-catenin, and concurrent Wnt/β-catenin pathway activation significantly enhances tumorigenesis in mouse models, consistent with recurrent Wnt pathway alterations noted in human tumors — leads to cooperative oncogenic transformation of hepatocytes (demonstrated in mouse models; inferred as cooperating rather than sole driver in humans; PNAS:1716483114).
  7. Neoplastic hepatocytes proliferate as large, eosinophilic, mitochondria-rich polygonal cells; concurrently, tumor cells (via TGF-β overexpression) induce stromal fibroblasts/myofibroblasts to deposit parallel lamellar collagen bands around cell nests — results in the pathognomonic fibrolamellar histologic architecture (mechanistically inferred from TGF-β overexpression data; direct causal proof in humans is largely histological/correlative).
  8. Metabolically, tumor cells upregulate glutaminase (GLS) and downregulate ornithine transcarbamylase and glutamine synthetase (GS) — leads to a net ammoniagenic phenotype that, in a subset of patients (often with high tumor burden), overwhelms residual (non-cirrhotic) hepatic ammonia clearance — resulting in the paraneoplastic hyperammonemic encephalopathy phenotype (demonstrated mechanistically at the tumor tissue level; PMC9922532).
  9. Neuroendocrine-gene overexpression, including neurotensin, provides an additional autocrine/paracrine source of cAMP and co-mitogenic signaling that may reinforce the PKA-driven proliferative loop (demonstrated in vitro; PMC6707953) — though neurotensin has not proven sufficiently sensitive/specific as a stand-alone clinical biomarker.
  10. Clinically, unchecked local growth leads to a large, well-circumscribed hepatic mass (often 5–20 cm) with a central fibrous scar, and given the typically late, nonspecific symptom presentation, a substantial fraction of patients progress to regional lymph-node and distant (lung, peritoneal, osseous) metastatic spread by diagnosis or shortly after resection (documented in surgical/SEER series; e-jlc.org, cco.amegroups.org).

Molecular Pathways

  • cAMP-PKA signaling (central driver pathway; KEGG hsa04024)
  • RAS/MAPK (RAF-MEK-ERK) cascade, aberrantly scaffolded by AKAP-Lbc
  • SIK-CRTC2-CREB/p300 transcriptional coactivation axis
  • Wnt/β-catenin signaling (cooperating pathway)
  • AURKA-GSK3-MYC proliferative axis

Suggested GO terms: GO:0007188 (adenylate-cyclase-activating G protein-coupled receptor signaling pathway), GO:0004691 (cAMP-dependent protein kinase activity), GO:0060070 (canonical Wnt signaling pathway), GO:0000165 (MAPK cascade), GO:0016575 (histone deacetylation — inverse relevant to acetylation increase), GO:0006541 (glutamine metabolic process, for the hyperammonemia axis).

Cellular Processes

  • Sustained hepatocyte proliferation and impaired terminal differentiation
  • TGF-β–driven activation of hepatic stellate cells/portal fibroblasts producing the lamellar fibrotic stroma
  • Altered mitochondrial biogenesis (tumor cells are notably mitochondria-rich, contributing to the granular eosinophilic cytoplasm seen histologically)
  • Neuroendocrine transdifferentiation/gene expression program (neurotensin and related genes)

Protein Dysfunction

The DNAJB1-PRKACA fusion protein represents a gain-of-function, neomorphic chimeric kinase — not simple PKA overactivity but a structurally altered holoenzyme with novel scaffolding and allosteric properties (PMC7793292). This is best captured in dismech schema terms as functional_impact_category: NEOMORPHIC on the fusion's genetic_context.

Metabolic Changes

Dysregulated nitrogen/ammonia handling (GLS↑, OTC↓, GS↓) as detailed above; broader metabolomic characterization (lipidomic, amino-acid flux) is less well established in the literature retrieved here.

Immune System Involvement

FLC tumors and their microenvironment have been targeted by immunotherapy approaches (see Treatment), and rewired cell-to-cell communication signaling — including SPP1-CD44, MIF-ACKR3, GDF15-TGFBR2, and FGF7-FGFR axes — has been identified via single-cell multi-omic analysis, implicating altered tumor-immune and tumor-stromal crosstalk (bioRxiv 2024.12.11.627911).

Tissue Damage / Structural Formation Mechanisms

TGF-β overexpression is implicated in driving the characteristic lamellar fibrosis — parallel bands of collagen encircling tumor cell nests — a pattern distinct from cirrhotic fibrosis and specific to this tumor's stroma-tumor interaction (ScienceDirect S0740257016301162).

Molecular Profiling Summary

  • Transcriptomics: Neuroendocrine gene overexpression (including neurotensin) among the most significantly overexpressed genes; single-nucleus RNA-seq has mapped cell-type-specific expression programs (2024–2025 studies).
  • Epigenomics: snATAC-seq has resolved FLC-specific chromatin accessibility and super-enhancer landscapes (CDH11, SLC16A14 loci).
  • Genomics: Low overall mutation burden; the founding 19p13.12 deletion/fusion is essentially the sole recurrent structural event (PMC4359253).
  • Single-cell/spatial: 2024 multi-omic single-nucleus study is the most advanced published dataset, revealing rewired intercellular signaling (SPP1-CD44, MIF-ACKR3, GDF15-TGFBR2, FGF7-FGFR).
  • Functional genomics: In vitro drug screens have nominated HDAC inhibitors, topoisomerase I inhibitors, and the STAT3 inhibitor napabucasin as active compounds, with synergy reported when combined with Bcl-xL inhibition (Molecular Therapy, cell.com S1525-0016(23)00664-0).

7. Anatomical Structures Affected

Organ level: - Primary organ: Liver (hepatic parenchyma), typically arising as a solitary large mass, often in the left lobe in a substantial proportion of cases (per multiple imaging series). - Secondary/metastatic involvement: Regional (hilar, celiac, mediastinal) and distant lymph nodes; lungs; peritoneum; bone; less commonly pancreas, ovary, and — rarely — cardiac/right atrial extension via IVC. - Body systems: Primarily hepatobiliary/digestive system; secondary lymphatic and, in metastatic disease, respiratory and skeletal systems.

Suggested UBERON terms: UBERON:0002107 (liver), UBERON:0002370 (thymus – n/a), UBERON:0000029 (lymph node), UBERON:0002048 (lung), UBERON:0001474 (bone element), UBERON:0000992 (ovary).

Tissue and cell level: - Tumor cells are large, polygonal, hepatocyte-derived (or hepatic-progenitor-derived) neoplastic epithelial cells (CL:0000182 hepatocyte, or a progenitor-like cell type given ongoing debate about cell-of-origin). - Stromal compartment: activated portal/stellate fibroblasts producing lamellar collagen (CL:0000057 fibroblast; CL:0000632 hepatic stellate cell as a candidate contributor). - CD68+ macrophage-lineage co-expression pattern is diagnostically notable in tumor cells themselves (aberrant marker expression rather than true macrophage infiltration is one interpretation; CL:0000235 macrophage marker used diagnostically).

Subcellular level: - Tumor cells are characteristically mitochondria-rich (GO:0005739 mitochondrion), contributing to granular eosinophilic cytoplasm. - Intracytoplasmic "pale bodies" (amphophilic, fibrinogen-containing inclusions) and "hyaline bodies" (smaller, intensely eosinophilic) are seen in roughly half of cases (AASLD Pathology Pearls; ScienceDirect S0740257016301162).

Localization: Typically a single large hepatic mass (5–20 cm); bilobar or multifocal presentation is less common. No established lateralization pattern beyond frequent left-lobe predominance noted in some imaging series.

8. Temporal Development

  • Onset: Adolescent/young-adult onset is classic (peak ~15–19 years in registry data), with a smaller elderly-onset peak (~70–74 years); reported age range 2–74 years (npj Precision Oncology 2023).
  • Onset pattern: Insidious — symptoms (abdominal pain, distension, malaise) typically develop gradually over weeks to months before diagnosis, contributing to advanced stage at presentation.
  • Disease stages: No FLC-specific staging system exists; conventional HCC/AJCC liver staging or the Milan-type resectability framework is generally applied, alongside surgical categorization into resectable vs. unresectable/advanced disease.
  • Progression rate: Variable but often aggressive once metastatic; recurrence after resection is common — reported in up to 86% of patients in some surgical series (Yamashita et al., cited in cco.amegroups.org review).
  • Disease course pattern: Typically progressive with a high rate of locoregional and distant recurrence; not classically relapsing-remitting.
  • Remission patterns: Surgical resection (with negative margins) offers the only realistic chance of durable remission; spontaneous remission is not described. Recurrence, when resectable again, can still yield meaningful survival benefit (median OS 122 months with repeat resection of recurrence vs. 37 months without, per the Yamashita series).
  • Critical periods: Early surgical intervention while disease remains resectable is the single most important modifiable window; delayed diagnosis due to nonspecific symptoms is a major driver of poor outcomes.

9. Inheritance and Population

Epidemiology

  • Incidence: Age-adjusted U.S. incidence is approximately 0.02 per 100,000 person-years, roughly 100-fold lower than the ~1.99 per 100,000 annual incidence of conventional HCC (npj Precision Oncology 2023).
  • FLC represents ~1–2% of all hepatocellular carcinoma cases in the U.S. (PubMed:32052215; Fibrofoundation).
  • A 2023 computational/tiered clinical-data analysis suggests true incidence may be 5- to 8-fold higher than prior registry-based estimates, implying substantial historical under-ascertainment (PMC10034241/npj Precision Oncology 2023).
  • Bimodal age distribution: incidence peaks at ages 15–19 and 70–74.

Inheritance Pattern

FLC is essentially sporadic, driven by a somatic (non-inherited) DNAJB1-PRKACA fusion. No Mendelian inheritance pattern, penetrance, expressivity, anticipation, germline mosaicism, founder-effect, or carrier-frequency data apply in the conventional sense, since the causal lesion is not transmitted through the germline. A single case report of concurrent germline + somatic TP53 mutation raises a hypothesis-generating (not established) link to Li-Fraumeni-spectrum tumors in rare instances (Familial Cancer 2017), but this is not a recognized recurrent inheritance mechanism for FLC as a class.

Population Demographics

  • Race/ethnicity: >85% non-Hispanic white in U.S. cohorts; ~6% Chinese American, ~4% Black, ~4% white Hispanic (PubMed:32052215).
  • Geographic distribution: No clearly defined endemic regions; most epidemiological data derive from U.S. (SEER, NCDB) cohorts, with case series also reported from Europe and Asia, though comparative incidence data outside the U.S. are sparse.
  • Sex ratio: No strong sex predominance is consistently reported in the largest series (contrasts with conventional HCC's male predominance), though some surgical-outcome cohorts note male sex as a favorable prognostic factor.
  • Age distribution: Predominantly adolescents/young adults, with a smaller elderly subgroup.

10. Diagnostics

Laboratory Tests

  • Alpha-fetoprotein (AFP): Characteristically normal — an important distinguishing feature from conventional HCC, where AFP is often elevated (emedicine.medscape.com/278354-workup).
  • Vitamin B12-binding globulin (transcobalamin): Elevated in some series (classic but not universally sensitive/specific marker).
  • Neurotensin: Elevated in a subset of patients but not sufficiently sensitive or specific for stand-alone diagnostic use (PMC search results synthesis).
  • Procalcitonin: A newly proposed (2025) candidate tumor biomarker for diagnosis and follow-up, based on case reports and a literature review (medRxiv 2025.11.18.25340286; PMC12907347) — still investigational.
  • Serum ammonia: Elevated in the rare hyperammonemic encephalopathy presentation.

Imaging Studies

  • CT: Large (7–20 cm), heterogeneous, hypervascular, well-defined lobulated mass; central non-enhancing stellate scar in >80% of tumors at diagnosis; calcifications in 33–68% of cases, usually within the central scar (AJR 10.2214/AJR.13.11117; PMC4112400).
  • MRI: Near-isointense to liver on T1, hyperintense on T2; central scar is hypointense on both T1 and T2 (a helpful distinguishing feature from focal nodular hyperplasia, whose central scar is typically T2-hyperintense and lacks calcification).
  • Distinguishing FNH vs. FLC: Low T2 signal intensity and presence of calcification in the central scar favor FLC over FNH.

Biopsy/Pathology

  • Histopathology: Large polygonal/spindled cells with abundant granular eosinophilic cytoplasm, vesicular nuclei, prominent macronucleoli; paucicellular fibrous stroma in parallel lamellae; pale bodies/hyaline bodies in ~50% of cases.
  • Immunohistochemistry: CK7 and CD68 co-expression — when combined with compatible morphology, this combination is considered diagnostic of FLC (PMC search synthesis).

Molecular/Genetic Testing

  • Break-apart FISH for PRKACA rearrangement: Positive in 99% (102/103) of classic FLC cases in the largest multicenter validation study; a clinically validated, high-sensitivity/specificity assay (PubMed:35777788).
  • RT-PCR for DNAJB1-PRKACA fusion transcript: Successful detection in 92% (24/26) of tested cases; fusion transcript essentially specific to FLC among primary liver tumors tested, though shared with rare oncocytic pancreatobiliary neoplasms (PMC5758901; Modern Pathology 2019).
  • Targeted NGS fusion panels (e.g., MSK-IMPACT/MSK-Fusion hybridization-capture assays) are used clinically to detect the fusion (search synthesis).
  • Commercial clinical assay example: Mayo Clinic Laboratories' PRKAF test (FISH for PRKACA rearrangement, tissue-based).

Clinical Criteria / Differential Diagnosis

No DSM/ICD-based diagnostic criteria apply (this is a solid-organ malignancy); diagnosis rests on the combination of clinical context (young patient, no cirrhosis, normal AFP), imaging (central scar with calcification), histology, and CK7/CD68 IHC, confirmed by DNAJB1-PRKACA fusion testing (FISH, RT-PCR, or NGS). Key differentials: focal nodular hyperplasia (shares central scar but lacks fusion/calcification pattern), conventional HCC, hepatocellular adenoma, and other oncocytic hepatobiliary/pancreatic tumors that can rarely share the fusion.

Screening

No population or genetic screening program exists for FLC, consistent with its sporadic, non-heritable molecular basis and rarity.

11. Outcome/Prognosis

Survival Statistics (SEER/NCDB-based)

  • Overall median survival: ~24.5 months in a recent SEER cohort analysis (JCO 2024.42.16_suppl.e16213); considerably better in surgically managed patients (median survival ~75 months) (Dove Medical Press IJGM).
  • Age-stratified survival (SEER, n=225): Median survival 85 months for patients ≤19 years; 29 months for ages 20–59; 12 months for ages ≥60 — indicating younger age is strongly favorably prognostic (search synthesis of SEER analyses).
  • Stage-dependent survival: 1-year OS 67–100%; 5-year OS 28–65% across series; 5-year OS ~80% for resectable disease vs. ~10% for advanced/unresectable disease (systematic review/meta-analysis, PMC10073062).
  • Surgical outcome comparison: 3-year survival ~100% after liver resection vs. ~76% after liver transplantation in one comparative series (search synthesis).

Prognostic Factors

  • Favorable: Male sex, younger age, white race, surgical resectability, combined liver + lymph node resection (vs. liver resection alone).
  • Unfavorable: Vascular invasion, lymph node metastasis, advanced/unresectable disease at diagnosis, older age at diagnosis.

Recurrence

Recurrence after resection is common — reported in 86% of patients in one series (Yamashita et al.) — most frequently to intra-abdominal/intrathoracic lymph nodes, liver, lungs, and peritoneum. Notably, surgical resection of recurrent disease is associated with substantially improved median OS (122 months) compared to non-surgical management of recurrence (37 months), underscoring an aggressive surgical approach even at relapse.

Morbidity

Beyond mortality, morbidity includes recurrent surgical burden, paraneoplastic hyperammonemic encephalopathy (potentially severe/refractory), and — rarely — thromboembolic and cardiac complications from tumor extension. Systematic QoL outcome data (EQ-5D/PROMIS) specific to FLC were not identified in this search.

12. Treatment

Surgical/Interventional (Mainstay)

  • Surgical resection remains the only potentially curative modality and the single most important determinant of outcome, with 5-year OS of 50–76% in resected cohorts (cco.amegroups.org). NCIT: NCIT:C15329 (Surgical Procedure); more specific NCIT:C158** hepatectomy-type terms as applicable.
  • Orthotopic liver transplantation (OLT): Reserved for selected unresectable cases; outcomes are generally inferior to resection (3-year survival ~76% vs. ~100% for resection in comparative data), but transplantation (including living-donor transplant) has been reported even in cases with hilar lymph node metastasis (PubMed:29633928).
  • Lymphadenectomy: Combined liver resection + lymph node dissection is associated with better survival than liver resection alone, reflecting the disease's propensity for nodal spread.
  • Re-resection of recurrence: Associated with markedly improved survival versus non-operative management of relapse (see Outcome section).

Pharmacotherapy — No Established Standard of Care

There is no FDA-approved systemic therapy specific to FLC; conventional HCC systemic regimens (sorafenib, lenvatinib, other multikinase inhibitors) have shown limited/inconsistent efficacy, reflecting FLC's distinct molecular biology.

Immunotherapy

  • Checkpoint inhibitor combinations: Case reports describe tumor control with atezolizumab + bevacizumab re-administration (PMC11659117).
  • Nivolumab + fluorouracil + interferon alfa-2b: Active phase I/II trial at MD Anderson (NCT04380545) for unresectable FLC, estimated primary completion 2028 (NCIT:C2963 for immune checkpoint inhibitor class; therapeutic_agent CHEBI/NCIT terms for nivolumab, 5-FU, interferon alfa-2b).
  • Therapeutic peptide vaccine (2025 landmark trial): A phase 1 trial of a DNAJB1-PRKACA fusion-neoantigen peptide vaccine, combined with nivolumab + ipilimumab, was reported safe with encouraging early efficacy — disease control rate 75% (9/12) in patients completing the priming phase, including 3 partial responses (25%) (Nature Medicine 2025, 10.1038/s41591-025-03995-y). This is the first therapy directly targeting the fusion neoantigen immunologically and represents the most significant recent (2025) treatment advance.

Targeted/Experimental Therapies

  • ENMD-2076 (oral Aurora A kinase/VEGFR/FLT3/FGFR3 inhibitor): Phase 2 multicenter trial (NCT02234986) met its Stage 1 non-futility endpoint and advanced to Stage 2, but final results were modest — only 1/N (3%) partial response, 57% stable disease — insufficient to support further single-agent development (PubMed:32154962; CASI Pharmaceuticals press releases). Rationale was AURKA overexpression downstream of the fusion.
  • DT2216 (Bcl-xL-targeting PROTAC/degrader) + irinotecan: Phase I/II trial (NCT06620302) for relapsed/refractory pediatric, adolescent, and young-adult solid tumors including FLC, building on preclinical synergy between Bcl-xL inhibition and HDAC/topoisomerase I inhibitors/napabucasin (Fibrofoundation; Molecular Therapy 2023).
  • Napabucasin (STAT3/cancer-stemness inhibitor), HDAC inhibitors, and topoisomerase I inhibitors showed the most potent activity in a preclinical drug screen ("preclinical magic bullet" study), with synergy when combined with Bcl-xL inhibition — supporting the DT2216 combination trial rationale (Molecular Therapy 2023, S1525-0016(23)00664-0).
  • CRTC2/p300 targeting: Nominated as a therapeutic strategy following the 2024 mechanistic discovery of SIK inactivation/CRTC2-p300 deregulation by the fusion kinase (Cancer Discovery 2024) — not yet in clinical testing per available search results.

Supportive Care

Management of paraneoplastic hyperammonemic encephalopathy (a proposed treatment algorithm exists in the literature — PMC4828114) typically involves ammonia-lowering strategies (e.g., lactulose, rifaximin, sometimes dialysis/CRRT) alongside tumor-directed therapy, since standard cirrhosis-based hyperammonemia treatments may be less effective given the tumor-intrinsic ammoniagenic mechanism.

Treatment Algorithm Summary

  1. Assess resectability at diagnosis (imaging + multidisciplinary review).
  2. If resectable: hepatic resection + regional lymphadenectomy — curative-intent, best survival outcomes.
  3. If borderline/unresectable: consider liver transplantation in selected cases; consider clinical trial enrollment (peptide vaccine + checkpoint inhibitors, nivolumab-based regimens, DT2216 combinations).
  4. At recurrence: re-resection where feasible, given demonstrated survival benefit; otherwise systemic/experimental therapy.
  5. Manage paraneoplastic complications (notably hyperammonemic encephalopathy) proactively.

Suggested NCIT terms: NCIT:C15329 (Surgical Procedure), NCIT:C15289 (Organ Transplantation), NCIT:C1647 (Nivolumab), NCIT:C2039 (Ipilimumab — verify code), NCIT:C328 (Interferon alfa-2b — verify code), NCIT:C561 (Fluorouracil), NCIT:C15346 (Vaccination, for the peptide vaccine), NCIT:C15632 (Chemotherapy).

13. Prevention

  • Primary prevention: None established, since there are no modifiable environmental/lifestyle risk factors and the driver mutation is a sporadic somatic event.
  • Secondary prevention/screening: No population or genetic screening program exists; early recognition depends on clinical suspicion in young patients presenting with an incidental hepatic mass, especially with the CT/MRI central-scar-with-calcification pattern and normal AFP.
  • Tertiary prevention: Post-resection surveillance imaging is standard practice to detect recurrence early, given the high (up to 86%) recurrence rate and the demonstrated survival benefit of re-resection.
  • Genetic counseling: Not routinely indicated given the sporadic, somatic nature of the disease; would only be considered in the rare context of a suspected co-occurring germline cancer-predisposition syndrome (e.g., the isolated TP53/Li-Fraumeni-spectrum case report).
  • Public health/environmental interventions: Not applicable, as no environmental driver has been identified.

14. Other Species / Natural Disease

The literature retrieved in this search did not identify well-characterized naturally occurring FLC in companion animals or wildlife (unlike some other cancers with recognized veterinary correlates via OMIA). FLC-like disease in other species has not been prominently reported in the sources found. Genetically engineered animal models (see below) are the primary cross-species research tool, rather than natural veterinary disease. (This is a gap that would benefit from a dedicated OMIA/veterinary-literature search if higher confidence is needed.)

15. Model Organisms

Genetically Engineered Mouse Models

  • Transgenic/genetically engineered mouse models expressing DNAJB1-PKA(c) in the liver have been developed; initial adult-liver expression models produced FLC-resembling tumors but at low penetrance (bioRxiv 2023.12.06.569624; PMC11582006).
  • Mouse models combining DNAJB1-PRKACA expression with β-catenin activation show significantly enhanced tumorigenesis, supporting a two-hit cooperative model relevant to human Wnt-pathway alterations (PNAS:1716483114; PubMed:29162699).

Zebrafish Models

A zebrafish model expressing the DNAJB1-PRKACA fusion has been used to study fusion-induced liver inflammation as an early step in FLC pathogenesis (bioRxiv 781583).

Patient-Derived Models

  • Patient-derived xenografts (PDX) established from patient tumor tissue or ascites in immunocompromised mice, and PDX-derived organoids composed of FLC epithelial cells, endothelial progenitor cells, and stellate cells, have been developed by several research groups (PMC11582006).
  • CRISPR/Cas9-engineered ex vivo hepatocyte models: Mature hepatocytes edited to express the fusion gene (and, in some models, additional FLC-associated mutations) to generate FLC-like cells for mechanistic and drug-screening studies.
  • A commercial PDX model (Crown Bio's LI5132) is available for liver cancer/FLC-relevant preclinical drug testing.

Model Limitations

Current models — particularly the low-penetrance transgenic mouse — do not fully recapitulate the human disease's histology (lamellar fibrosis), long latency, and metastatic behavior; PDX/organoid models better preserve tumor-stroma heterogeneity but are lower-throughput and harder to scale for large drug screens. The Aurora kinase inhibitor ENMD-2076, effective in some preclinical models, translated to only modest clinical activity, illustrating a translational fidelity gap.

Research Applications

These models collectively support: (1) validation of the DNAJB1-PRKACA fusion as a necessary/sufficient driver, (2) testing of cooperating mutations (β-catenin), (3) mechanistic dissection of the SIK-CRTC2-p300 axis and AURKA/MYC network, and (4) preclinical drug screening (napabucasin, HDAC inhibitors, topoisomerase I inhibitors, Bcl-xL degraders such as DT2216).

Summary of Key Ontology Term Suggestions

Category Term
MONDO MONDO:0006210 (Fibrolamellar hepatocellular carcinoma)
Orphanet ORPHA:401920
Gene HGNC:9380 (PRKACA), HGNC:14887 (DNAJB1), HGNC:11998 (TP53)
GO (molecular function) GO:0004691 (cAMP-dependent protein kinase activity)
GO (biological process) GO:0060070 (canonical Wnt signaling), GO:0000165 (MAPK cascade), GO:0006541 (glutamine metabolic process)
GO (cellular component) GO:0005739 (mitochondrion)
CL CL:0000182 (hepatocyte), CL:0000057 (fibroblast)
UBERON UBERON:0002107 (liver), UBERON:0000029 (lymph node), UBERON:0002048 (lung)
HP HP:0002240 (Hepatomegaly), HP:0002027 (Abdominal pain), HP:0000771 (Gynecomastia), HP:0001982 (Hyperammonemia), HP:0000952 (Jaundice)
NCIT (treatment) NCIT:C15329 (Surgical Procedure), NCIT:C15289 (Organ Transplantation), NCIT:C15632 (Chemotherapy), NCIT:C15346 (Vaccination)
CHEBI (fluorouracil, therapeutic agents — verify specific CHEBI IDs before curation)

Notable Evidence Gaps / Curation Cautions

  1. CTNNB1 mutation frequency in human FLC — the mouse-model cooperation with β-catenin is well documented, but a precise human-cohort mutation frequency was not retrievable in this pass and should be verified against the primary genomic-landscape papers (Oncotarget 2015; subsequent cohort studies) before citing a specific percentage.
  2. DNAJB1-PRKACA specificity — not absolutely exclusive to FLC (also found in oncocytic pancreatobiliary neoplasms); curation should qualify "pathognomonic" claims accordingly.
  3. Natural veterinary disease — no strong evidence of naturally occurring FLC in other species was found; this section should be flagged as a gap rather than asserted as "none exists" without a dedicated OMIA search.
  4. Quantitative QoL data (EQ-5D/SF-36/PROMIS) specific to FLC patients were not identified and likely do not exist in validated form.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 35
Resolved 35
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 35
On topic 21
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 54
Resolved 38
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 14
Terms whose name was checked 22
Terms named correctly 16
Terms named as a different term 3
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0006210 (3 mentions) - the report calls it "if available", "Fibrolamellar hepatocellular carcinoma"; MONDO calls it fibrolamellar hepatocellular carcinoma
  • HP:0033834 (1 mention) - the report calls it "Fatigue-related"; HP calls it Malaise
  • GO:0016575 (2 mentions) - the report calls it "histone deacetylation, inverse direction relevant", "histone deacetylation — inverse relevant to acetylation increase"; GO calls it obsolete histone deacetylation

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • NCIT:C158 (1 mention) - NCIT does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0016575 (obsolete histone deacetylation) (2 mentions)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0007188 (1 mention) - the report calls it "adenylate-cyclase-activating G protein-coupled receptor signaling pathway"; GO calls it adenylate cyclase-modulating G protein-coupled receptor signaling pathway
  • GO:0006541 (2 mentions) - the report calls it "glutamine metabolic process, for the hyperammonemia axis"; GO calls it L-glutamine metabolic process
  • UBERON:0002370 (1 mention) - the report calls it "thymus – n/a"; UBERON calls it thymus

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0006210 - called "if available", "Fibrolamellar hepatocellular carcinoma"
  • GO:0016575 - called "histone deacetylation, inverse direction relevant", "histone deacetylation — inverse relevant to acetylation increase"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, PubMed, PNAS, Oncotarget.