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

We selected eight of these genes (CA12, FAM19A5, HSPA1B, LINC00473, OAT, SLC16A14, TESC, and VCAN) for further investigation. We chose SLC16A14 and LINC00473 because they have high densities of FLC-specific enhancers with FOSL2/JUN (Fig. 3D ) and CREB motifs (Fig. 3E ), respectively; FAM19A5 because it has the greatest number of significantly correlated enhancers (Fig. 4G) ; TESC and VCAN because they have previously been strongly implicated in drug resistance Li et al., 2017; Man et al., 2014) , a salient feature of FLC (Maniaci et al., 2009; Torbenson, 2012) ; CA12 and OAT The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.01.18.911297 doi: bioRxiv preprint because we have previously identified them as candidate markers of FLC (Dinh et al., 2017) and because CA12 is a prominent mediator of drug resistance in other cancer types (Boyd et al., 2017; Doyen et al., 2013; Kopecka et al., 2016; Yoo et al., 2010) ; and HSPA1B because it encodes a member of the heat shock protein 70 (HSP70) family, which has been shown to interact with the DNAJB1-PRKACA fusion found in FLC . We also selected one gene that only appears in the FLC-specific enhancer hotspot analysis (RPS6KA2) and another from the gene-enhancer correlation (FZD10) analysis for further investigation (Fig. 6A) .