title: A genomic case study of mixed fibrolamellar hepatocellular carcinoma.
abstract: Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components, represents up to 25% of cases of FL-HCC, and has been associated with worse prognosis. Recent genomic characterization of pure FL-HCC identified a highly recurrent transcript fusion (DNAJB1:PRKACA) not found in conventional HCC.
  
  
  
  We performed exome and transcriptome sequencing of a case of mFL-HCC. A novel BAC-capture approach was developed to identify a 400 kb deletion as the underlying genomic mechanism for a DNAJB1:PRKACA fusion in this case. A sensitive Nanostring Elements assay was used to screen for this transcript fusion in a second case of mFL-HCC, 112 additional HCC samples and 44 adjacent non-tumor liver samples.
  
  
  
  We report the first comprehensive genomic analysis of a case of mFL-HCC. No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples.
  
  
  
  These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and mFL-HCC.
authors.affiliation: McDonnell Genome Institute; Department of Medicine; Siteman Cancer Center; Department of Genetics. Electronic address: obigriffith@wustl.edu.
authors.forename: O L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: McDonnell Genome Institute; Siteman Cancer Center; Department of Genetics.
authors.forename: M
authors.initials: M
authors.lastname: Griffith
authors.affiliation: McDonnell Genome Institute.
authors.forename: K
authors.initials: K
authors.lastname: Krysiak
authors.affiliation: McDonnell Genome Institute; Department of Genetics.
authors.forename: V
authors.initials: V
authors.lastname: Magrini
authors.affiliation: McDonnell Genome Institute.
authors.forename: A
authors.initials: A
authors.lastname: Ramu
authors.affiliation: McDonnell Genome Institute.
authors.forename: Z L
authors.initials: ZL
authors.lastname: Skidmore
authors.affiliation: McDonnell Genome Institute.
authors.forename: J
authors.initials: J
authors.lastname: Kunisaki
authors.affiliation: McDonnell Genome Institute.
authors.forename: R
authors.initials: R
authors.lastname: Austin
authors.affiliation: McDonnell Genome Institute.
authors.forename: S
authors.initials: S
authors.lastname: McGrath
authors.affiliation: McDonnell Genome Institute.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: McDonnell Genome Institute.
authors.forename: R
authors.initials: R
authors.lastname: Demeter
authors.affiliation: McDonnell Genome Institute.
authors.forename: T
authors.initials: T
authors.lastname: Graves
authors.affiliation: McDonnell Genome Institute.
authors.forename: J M
authors.initials: JM
authors.lastname: Eldred
authors.affiliation: McDonnell Genome Institute.
authors.forename: J
authors.initials: J
authors.lastname: Walker
authors.affiliation: McDonnell Genome Institute; Department of Genetics.
authors.forename: D E
authors.initials: DE
authors.lastname: Larson
authors.affiliation: McDonnell Genome Institute; Department of Medicine; Siteman Cancer Center.
authors.forename: C A
authors.initials: CA
authors.lastname: Maher
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis.
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis.
authors.forename: W
authors.initials: W
authors.lastname: Chapman
authors.affiliation: Departments of Radiation Oncology.
authors.forename: A
authors.initials: A
authors.lastname: Mahadevan
authors.affiliation: Medicine.
authors.forename: R
authors.initials: R
authors.lastname: Miksad
authors.affiliation: Pathology, Harvard Medical School, Boston.
authors.forename: I
authors.initials: I
authors.lastname: Nasser
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Hanto
authors.affiliation: McDonnell Genome Institute; Department of Medicine; Siteman Cancer Center; Department of Genetics.
authors.forename: E R
authors.initials: ER
authors.lastname: Mardis
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
chemical_list: C494647:DNAJB1 protein, human; D050956:HSP40 Heat-Shock Proteins; D015514:Oncogene Proteins, Fusion; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human
keywords: DNAJB1:PRKACA; fusion transcript; genome analysis; mixed fibrolamellar hepatocellular carcinoma