Fibrolamellar Hepatocellular Carcinoma: Mechanistic Distinction From Adult Hepatocellular Carcinoma

Riggle, Kevin M.; Turnham, Rigney; Scott, John D.; Yeung, Raymond S.; Riehle, Kimberly J.

doi:10.1002/pbc.25970

Cited by 51 publications

(52 citation statements)

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“…Although widely used in clinical practice, none of the proposed markers are actually specific for fibrolamellar hepatocellular carcinoma and their diagnostic significance is therefore limited 38 . Mouse FL-HCC expressed high levels of hepatocytes markers (CEA and HepPar1) and displayed scattered positivity for the biliary epithelium marker cytokeratin 7 and a stronger staining for cytokeratin 19, a marker associated with both biliary differentiation and hepatic progenitors.…”

Section: Discussionmentioning

confidence: 99%

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CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

et al. 2017

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Background & Aims Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1–PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1–Prkaca fusion and monitored the mice for liver tumor development. Methods We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1–Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8 week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1–Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing. Results 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 tumors contained the Dnajb1–Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1–Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC. Conclusions Using CRISPR/Cas9 technology, we found generation of the Dnajb1–Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1–PRKACA might be developed as therapeutics for this form of liver cancer.

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Section: Discussionmentioning

confidence: 99%

“…Indeed, testing of DNAJB1–PRKACA mRNA or protein as a drug target in FL-HCC is highly warranted 38 . DNAJB1–PRKACA could prove as excellent a drug target as the BCR-ABL1 fusion in chronic myeloid leukemia, where a single, oncogenic event elicits and drives the disease and predicts a very favorable response to its inhibition 41 .…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

et al. 2017

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“…Although often described as a relatively indolent disease, a high rate of recurrence represents a major clinical challenge (11) and the 5-year survival rate is 34% (12). There is no evidence of survival benefit from adjuvant chemotherapy or any systemic treatment applicable to classic HCC (13). The unique demographics and genetics of FL-HCC suggest that these patients should be treated differently than those harboring HCC, The segmental deletion that results in the DNAJB1-PRKACA gene fusion entails heterozygous loss of 7 other coding genes, with unknown functional contribution.…”

Section: Introductionmentioning

confidence: 99%

DNAJB1-PRKACAfusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma

Kastenhuber

Lalazar

Tschaharganeh

et al. 2017

Preprint

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A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here, we implement CRISPR/Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of both the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, 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. Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes tissue injury, inflammation and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC and establishes a practical model for preclinical studies to identify strategies to treat this disease. SignificanceEfforts to understand and treat FL-HCC have been confounded by a lack of models that accurately reflect the genetics and biology of the disease. Here, we demonstrate that the Dnajb1-Prkaca gene fusion drives tumorigenesis in mice, and that fusion to DNAJB1 drives FL-HCC initiation more effectively than wild type PRKACA overexpression. The requirement of the PRKACA kinase domain in tumor initiation establishes the potential utility of kinase inhibitors targeting the fusion. By identifying genetic and environmental factors that can enhance the consistency and aggressiveness of disease progression, we reveal biological characteristics of the disease and advance a robust platform for future pre-clinical studies.

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“…Vimentin is an intermediate filament protein expressed in mesenchymal cells, which have been shown to promote metastasis and tumor growth in HCC . Based on immunophenotype (positive Arginase‐1), the HCC in the described case can be called “conventional” as opposed to the fibrolamellar type (FL‐HCC) termed primary HCC. FL‐HCC is characterized by the presence of well‐differentiated tumor cells, organized in cords, separated by fibrous lamellae, and comprises 1%‐9% of HCCs, affecting younger adults as compared to conventional HCC, which affects an older population .…”

Section: Discussionmentioning

confidence: 82%

“…71 which have been shown to promote metastasis and tumor growth in HCC. 32 Based on immunophenotype (positive Arginase-1), the HCC in the described case can be called "conventional" as opposed to the fibrolamellar type (FL-HCC) 72,73 termed primary HCC.…”

Section: Immuno-reactivity In Human Hcc Cases and In Nhp Tissuesmentioning

confidence: 99%

A first case of hepatocellular carcinoma in the baboon (Papio spp.) placenta

Schlabritz‐Loutsevitch

Carrillo

et al. 2018

J of Medical Primatology

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We present a case of hepatocellular carcinoma (HCC) in the placenta of healthy baboon (Papio spp.). Grossly, the fetal, maternal, and placental tissues were unremarkable. Histologically, the placenta contained an unencapsulated, poorly demarcated, infiltrative, solidly cellular neoplasm composed of cells that resembled hepatocytes. The neoplastic cells were diffusely positive for vimentin and focally positive for Ae1/Ae3, Arginase ‐1, glutamine synthetase, and CD10, and negative for ER, vascular markers (CD31 and D240), S100, glypican, C‐reactive protein, FABP, desmin, and beta‐catenin; INI1 positivity was similar to non‐neoplastic tissues. The case likely represents a unique subtype of HCC.

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Fibrolamellar Hepatocellular Carcinoma: Mechanistic Distinction From Adult Hepatocellular Carcinoma

Cited by 51 publications

References 50 publications

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

DNAJB1-PRKACAfusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma

A first case of hepatocellular carcinoma in the baboon (Papio spp.) placenta

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