FCF Funded Projects

Discovery of the chimera genetic mutation

Status: Completed

Timeframe: 2012 – 2014

Goal: Identify genetic mutations in FLC

Principal Investigator: Sandy Simon, PhD

Study background: The goal of this project was to identify genetic mutations present in FLC. The team used whole genome sequencing together with RNA sequencing to identify mutations in FLC tumors compared to their normal liver counterparts. Identification of mutations common in FLC tumors is critical to enhancing the understanding of the underlying biology of this tumor and allow for development of novel therapeutics.

Results and implications: This research ultimately resulted in the game-changing discovery of a unique genetic mutation, a chimeric gene, common to all fibrolamellar tissues studied.

In summary, the study:

  • whole-genome sequencing provided evidence of a 400 kb heterozygous deletion on chromosome 19 in ten out of ten FLC patients tested
  • whole-transcriptome analysis detected a chimeric DNAJB1- PRKACA RNA transcript in 12 of 12 patients tested, and
  • the fusion transcript was shown to encode a chimeric DNAJB1-PRKACA protein that couples a segment of the heat shock protein, DNAJB1, with the catalytic domain of protein kinase A (PKA) and exhibits full retention of PKA activity.

Neither the genomic deletion, the chimeric transcript, nor the chimera protein were present in any matched normal liver samples tested.

While the role of the DNAJB1-PRKACA chimera in the pathogenesis of FLC was not confirmed until later studies, this effort raised the possibility that it contributes to the pathogenesis of the tumor and may represent an important therapeutic target.

This research was conducted at the Tucker Davis Research Facility at Rockefeller University, led by Dr. Sandy Simon. His daughter Elana, a fibrolamellar patient, was a lead researcher. The results were published in the preeminent medical journal Science and reported in The Wall Street Journal, US News and World Report, AP, The Today Show, NBC Nightly News, and presented to President Obama.

Click here to read or download the resulting article “Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma”, published in February 2014.