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A genomic case study of mixed fibrolamellar hepatocellular carcinoma.


ABSTRACT: 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 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.

SUBMITTER: Griffith OL 

PROVIDER: S-EPMC4880064 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A genomic case study of mixed fibrolamellar hepatocellular carcinoma.

Griffith O L OL   Griffith M M   Krysiak K K   Magrini V V   Ramu A A   Skidmore Z L ZL   Kunisaki J J   Austin R R   McGrath S S   Zhang J J   Demeter R R   Graves T T   Eldred J M JM   Walker J J   Larson D E DE   Maher C A CA   Lin Y Y   Chapman W W   Mahadevan A A   Miksad R R   Nasser I I   Hanto D W DW   Mardis E R ER  

Annals of oncology : official journal of the European Society for Medical Oncology 20160330 6


<h4>Background</h4>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.<h4>Patients and methods</h4>We performed exome and transcriptome sequencing of a case of mFL-HCC.  ...[more]

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