Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance

Timothy A. Dinh; Ramja Sritharan; F. Donelson Smith; Adam B. Francisco; Rosanna K. Ma; Rodica P. Bunaciu; Matt Kanke; Charles G. Danko; Andrew P. Massa; John D. Scott; Praveen Sethupathy

In addition, we have demonstrated that CA12, SLC16A14, VCAN, and RPSK6A2 are responsive to DNAJB1-PRKACA in at least one of two different genetically engineered murine models of FLC. However, we did not notice a significant induction of expression for several of the other FLC enhancer-hotspot associated genes that we tested, even though they are over-expressed in primary FLC tumors. There are several possible explanations for this observation. First, the murine models we used might have species-specific differences in gene regulation compared to human. Second, these genes might not be directly downstream of DNAJB1-PRKACA, but induced due to another process during tumor initiation or progression. For example, certain genes may be induced during or in response to the development of tumor fibrosis within FLC tumors. Although this is a distinctive feature of primary human FLCs, current mouse models lack this characteristic, providing a possible explanation for the observed differences. While this is indicative of a critical need for better model systems, our results using two murine models suggest that at least CA12, SLC16A14, VCAN, and RPS6KA2 are responsive to DNAJB1-PRKACA. Alternative models may be necessary . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi. org/10.1101 org/10. /2020 to study the remaining genes. For example, since LINC00473 is a primate-specific lncRNA, we used the HepG2 cell line stably expressing DNAJB1-PRKACA to demonstrate LINC00473 is responsive to the fusion.