Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation

Eric C. Sorenson, Raya Khanin, Zubin M. Bamboat, Michael J. Cavnar, Teresa S. Kim, Eran Sadot, Shan Zeng, Jonathan Greer, Adrian M. Seifert, Noah A. Cohen, Megan H. Crawley, Benjamin L. Green, David S. Klimstra, Ronald P. DeMatteo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0176562
JournalPLoS One
Volume12
Issue number5
DOIs
Publication statusPublished - May 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sorenson, E. C., Khanin, R., Bamboat, Z. M., Cavnar, M. J., Kim, T. S., Sadot, E., ... DeMatteo, R. P. (2017). Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation. PLoS One, 12(5), [e0176562]. https://doi.org/10.1371/journal.pone.0176562