Griffith, O. L.Griffith, M.Krysiak, K.Magrini, V.Ramu, A.Skidmore, Z. L.Kunisaki, J.Austin, R.McGrath, S.Zhang, J.Demeter, R.Graves, T.Eldred, J. M.Walker, J.Larson, D. E.Maher, C. A.Lin, Y.Chapman, W.Mahadevan, A.Miksad, R.Nasser, I.Hanto, D. W.Mardis, E. R.2016-06-142016Griffith, O. L., M. Griffith, K. Krysiak, V. Magrini, A. Ramu, Z. L. Skidmore, J. Kunisaki, et al. 2016. “A genomic case study of mixed fibrolamellar hepatocellular carcinoma.” Annals of Oncology 27 (6): 1148-1154. doi:10.1093/annonc/mdw135. http://dx.doi.org/10.1093/annonc/mdw135.0923-7534http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320275Background: 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 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. 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.en-USmixed fibrolamellar hepatocellular carcinomagenome analysisfusion transcriptJournal Article2016-06-1410.1093/annonc/mdw135