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

Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that predominantly affects adolescents and young adults with no prior history of liver disease (Craig et al., 1980; Torbenson, 2012) . Currently, surgical resection is the only effective treatment for FLC, however most patients have metastatic disease at the time of diagnosis, making surgical cures difficult (Stipa et al., 2006) . While some patients have been successfully treated with chemotherapy and molecular therapies, there is no standard treatment regimen for FLC patients (Torbenson, 2012) . Furthermore, FLC is often drug resistant and frequently recurs following initial treatment (Maniaci et al., 2009) , underscoring the need to develop effective therapies for this cancer. FLC is genetically characterized by a ~400 kb heterozygous deletion on chromosome 19 that leads to the formation of the DNAJB1-PRKACA fusion (Honeyman et al., 2014) . This fusion occurs in at least 80% of patients (Cornella et al., 2014; Honeyman et al., 2014) , is specific to FLC (Dinh et al., 2017; Graham et al., 2015; Kastenhuber et al., 2017) , and is sufficient to drive liver tumor formation in mice (Engelholm et al., 2017; Kastenhuber et al., 2017) . Multiple groups have performed genome-scale analyses to identify dysregulated genes (Cornella et al., 2014; Dinh et al., 2017; Griffith et al., 2016; Malouf et al., 2014; Simon et al., 2015; Sorenson et al., 2017; Xu et al., 2014) , long non-coding RNAs (Dinh et al., 2017) , and microRNAs (Dinh et al., 2019; Farber et al., 2018) in FLC. Yet, little is known about the causative transcriptional regulatory mechanisms that lead to aberrant gene expression and FLC tumor formation.