FCF Funded Projects

Molecular analysis of FLC tumors

Status: Completed

Timeframe: 2013 – 2016

Goal: Conduct genomic-based analysis of FLC patients

Principal Investigator: Ron DeMatteo, MD

Study background and overview: At the time of this effort, little was known about the exact mutations driving fibrolamellar carcinoma. Published research on the genomic alterations in FLC was scarce and limited to small studies, with the largest comprised of just 11 patients.

Without this knowledge, clinicians were unable to design or apply targeted therapies to FLC. As a major referral center for liver cancer patients, Memorial Sloan-Kettering had a unique position to study FLC. The study team proposed to conduct a genomic-based analysis in the largest cohort of FLC patients to date, using tissue samples from approximately 40 FLC patients who underwent resection surgery for primary or metastatic fibrolamellar cancer. Their goal was to identify the causes and drivers of FLC – laying the groundwork for development of novel and more effective treatments.

Key findings: The study analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All the tumor specimens examined exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in the metastatic tumors. They observed the DNAJB1-PRKACA fusion transcript in 26 of 26 tumor specimens from 15 FL-HCC patients, further strengthening the belief that the DNAJB1-PRKACA fusion plays a key role in tumorigenesis.

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. Analysis of the transcriptome demonstrated a high degree of similarity in all tumors from the same patients, independent of the recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis, despite the lack of a TP53 inactivating mutation in FLC. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue.

These results were published in PLOS ONE in May 2017. The full article can be accessed at https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176562.

Implications: The study data indicates a role for p53 pathway inactivation and IGF2BP1 upregulation in FLC, both of which have important roles in conventional hepatocellular carcinoma pathogenesis as well. The results also suggest a mechanism for IGF2BP1 up regulation. The study also showed that FLC tumors are likely able to suppress p53 pathway activity by multiple alternative and potentially targetable means.

In addition, a case series on 37 patients with FLC treated at MSKCC was published in The British Journal of Radiology in April 2014. Details of that case study can be read here: https://www.birpublications.org/doi/10.1259/bjr.20140024.