Abstract
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.
Highlights
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most commonly occurs in young adults without a history of underlying liver disease [1, 2]
In 4 of 6 patients who had paired primary and metastatic tumor specimens available, genomic amplifications were more frequent in the metastases when compared with the matched primary tumors (Fig 1B)
We found that genomic amplifications and deletions are common in FL-HCC tumors, and that metastatic tumors have more genomic alterations than primary tumors
Summary
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most commonly occurs in young adults without a history of underlying liver disease [1, 2]. FL-HCC accounts for less than 1% of all primary liver malignancies and has nearly equal incidence among genders, with a mean age at diagnosis around 23–39 years [3, 4]. Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma collection and analysis, decision to publish, or preparation of the manuscript
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