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

To determine the uniqueness of the FLC-specific enhancer hotspots, we compared them to previously identified super enhancers in SEdb (Jiang et al., 2019) . This database contains 325,607 super enhancers from more than 540 human samples across over 240 cell and tissue types, including 14 from normal human liver, primary hepatocytes, and multiple cell lines including HepG2 and Huh7. We found that 10 FLC-specific enhancer hotspots are not present in any sample in SEdb. Notably, this includes those linked to SLC16A14 and FAM19A5 (Fig. 5F ,G; Table S5 ), indicating that the mechanisms of transcriptional regulation of these genes may be unique in FLC. FLC-specific enhancer hotspots associated with LINC00473 and CA12 showed minimal intersection with super enhancers in SEdb (Fig. 5G) , overlapping 12 and 37 super enhancers, respectively. Additionally, 72 FLC-specific enhancer hotspots, including those associated with LINC00473 and CA12, did not overlap with super enhancers from any of the 14 liver-derived samples, which include healthy liver and hepatocellular carcinoma cell lines.