Format

Send to

Choose Destination
Ann Oncol. 2016 Jun;27(6):1148-54. doi: 10.1093/annonc/mdw135. Epub 2016 Mar 30.

A genomic case study of mixed fibrolamellar hepatocellular carcinoma.

Author information

1
McDonnell Genome Institute Department of Medicine Siteman Cancer Center Department of Genetics obigriffith@wustl.edu.
2
McDonnell Genome Institute Siteman Cancer Center Department of Genetics.
3
McDonnell Genome Institute.
4
McDonnell Genome Institute Department of Genetics.
5
McDonnell Genome Institute Department of Medicine Siteman Cancer Center.
6
Department of Surgery, Washington University School of Medicine, St Louis.
7
Departments of Radiation Oncology.
8
Medicine.
9
Pathology, Harvard Medical School, Boston.
10
Department of Surgery, Vanderbilt University School of Medicine, Nashville, USA.
11
McDonnell Genome Institute Department of Medicine Siteman Cancer Center Department of Genetics.

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.

KEYWORDS:

DNAJB1:PRKACA; fusion transcript; genome analysis; mixed fibrolamellar hepatocellular carcinoma

PMID:
27029710
PMCID:
PMC4880064
DOI:
10.1093/annonc/mdw135
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center