A genomic case study of mixed fibrolamellar hepatocellular carcinoma

O. L. Griffith, M.Griffith, K.Krysiak, V.Magrini, A.Ramu, Z.L.Skidmore, J.Kunisaki, R.Austin, S.McGrath, J.Zhang, R.Demeter, T.Graves, J.M.Eldred, J.Walker, D.E.Larson, C.A.Maher, Y.Lin, W.Chapman, A.Mahadevan, R.MiksadI.Nasser, D.W.Hanto, E.R.Mardis

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14 Scopus citations


Background: 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. Patients and Methods: We performed exome and transcriptome sequencing of a case of mFL-HCC. A novel BACcapture 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1148-1154
Number of pages7
JournalAnnals of Oncology
Issue number6
StatePublished - Jun 18 2016


  • Fusion transcript
  • Genome analysis
  • Mixed fibrolamellar hepatocellular carcinoma


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