title: Genomic analysis of fibrolamellar hepatocellular carcinoma.
abstract: Pediatric tumors are relatively infrequent, but are often associated with significant lethality and lifelong morbidity. A major goal of pediatric cancer research has been to identify key drivers of tumorigenesis to eventually develop targeted therapies to enhance cure rate and minimize acute and long-term toxic effects. Here, we used genomic approaches to identify biomarkers and candidate drivers for fibrolamellar hepatocellular carcinoma (FL-HCC), a very rare subtype of pediatric liver cancer for which limited therapeutic options exist. In-depth genomic analyses of one tumor followed by immunohistochemistry validation on seven other tumors showed expression of neuroendocrine markers in FL-HCC. DNA and RNA sequencing data further showed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. The first, a 400 kb deletion, results in a DNAJB1-PRKCA fusion transcript, which leads to increased cAMP-dependent protein kinase (PKA) activity in the index tumor case and other FL-HCC cases compared with normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTM1L and GLIS3 genes, generates a transcript whose product also promotes cancer phenotypes in HCC cell lines. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.
authors.affiliation: Department of Pediatrics Department of Genetics and.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pediatrics Department of Pathology, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Florette K
authors.initials: FK
authors.lastname: Hazard
authors.affiliation: Department of Pediatrics Department of Genetics and.
authors.forename: Anne-Flore
authors.initials: AF
authors.lastname: Zmoos
authors.affiliation: Department of Pediatrics Department of Genetics and.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jahchan
authors.affiliation: Department of Genetics and.
authors.forename: Hassan
authors.initials: H
authors.lastname: Chaib
authors.affiliation: Department of Pediatrics Department of Genetics and.
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Garfin
authors.affiliation: Department of Pediatrics.
authors.forename: Arun
authors.initials: A
authors.lastname: Rangaswami
authors.affiliation: Department of Genetics and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Department of Pediatrics Department of Genetics and julsage@stanford.edu.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
mesh_terms: D000293:Adolescent; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D055106:Genome-Wide Association Study; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D017384:Sequence Deletion; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C422445:CLPTM1L protein, human; D004268:DNA-Binding Proteins; C494647:DNAJB1 protein, human; C512851:GLIS3 protein, human; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha