Genomic analysis of fibrolamellar hepatocellular carcinoma

Hum Mol Genet. 2015 Jan 1;24(1):50-63. doi: 10.1093/hmg/ddu418. Epub 2014 Aug 13.

Abstract

Pediatric tumors are relatively infrequent, but are often associated with significant lethality and lifelong morbidity. A major goal of pediatric cancer research has been to identify key drivers of tumorigenesis to eventually develop targeted therapies to enhance cure rate and minimize acute and long-term toxic effects. Here, we used genomic approaches to identify biomarkers and candidate drivers for fibrolamellar hepatocellular carcinoma (FL-HCC), a very rare subtype of pediatric liver cancer for which limited therapeutic options exist. In-depth genomic analyses of one tumor followed by immunohistochemistry validation on seven other tumors showed expression of neuroendocrine markers in FL-HCC. DNA and RNA sequencing data further showed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. The first, a 400 kb deletion, results in a DNAJB1-PRKCA fusion transcript, which leads to increased cAMP-dependent protein kinase (PKA) activity in the index tumor case and other FL-HCC cases compared with normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTM1L and GLIS3 genes, generates a transcript whose product also promotes cancer phenotypes in HCC cell lines. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Genome-Wide Association Study
  • HSP40 Heat-Shock Proteins / genetics*
  • HSP40 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Liver Neoplasms / genetics*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Protein Kinase C-alpha / genetics*
  • Protein Kinase C-alpha / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • Sequence Deletion
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Translocation, Genetic

Substances

  • CLPTM1L protein, human
  • DNAJB1 protein, human
  • GLIS3 protein, human
  • HSP40 Heat-Shock Proteins
  • Membrane Proteins
  • Neoplasm Proteins
  • Recombinant Fusion Proteins
  • Transcription Factors
  • PRKCA protein, human
  • Protein Kinase C-alpha

Supplementary concepts

  • Fibrolamellar hepatocellular carcinoma