Fibrolamellar carcinoma as a distinct subtype of hepatocellular carcinoma: molecular genetics features, diagnostics and treatment prospects

Fibrolamellar carcinonoma (FLC) was described in 1956 as a separate subtype of hepatocellular carcinoma (HCC) that affects young adults without underling liver diseases. Morphologically FLC is characterized as HCC with large cells, gross nucleus and fibrous collagen bands organized into branched net. The mechanisms of FLC development in the absence of major risk factors remained obscured for a considerable amount of time. High-throughput transcriptomic analysis allowed to describe the unique profile of gene expression in FLC and to define the main signaling pathways activated in tumor cells which include mTOR, FGFR и EGFR cascades which can be accounted as potential therapeutic targets for this type of tumors. Whole transcriptome sequencing allowed to identify in the majority of FLC samples the new chimeric transcript DNAJB1-PRKACA which appears due to deletion of the part of chromosome 19 which leads to fusion of two genes. This translocation appears to be driving event in FLC development that governs increase of proliferation, colony formation and tumor stem cells population. Fusion transcript is specific for FLC and can be identified through the number of clinical laboratory methods. It opens the opportunity for use of that fusion in differential diagnostics as FLC marker. Due to kinase activity of DNAJB1-PRKACA protein, it is considered to be prospective target for the development of therapeutic compounds which can inhibit this function. Analysis of transcriptome aberrations in FLC allowed to specify the prognostic signature of 8 genes whose overexpression correlates with poor patient survival after the surgery. In this review we have summarized recent data on FLC molecular pathogenesis and possibilities for the development of new methods for diagnosis and treatment based on these findings.