Fibrolamellar hepatocellular carcinoma is a rare, malignant liver
tumor that often arises in the otherwise normal liver of adolescents and young adults. Previous studies have focused on
biomarkers and comparisons to traditional
hepatocellular carcinoma, and have yielded little data on the underlying pathophysiology. We performed whole genome sequencing on paired
tumor and normal samples from 10 patients to identify recurrent mutations and structural variations that could predispose to
oncogenesis. There are relatively few coding, somatic mutations in this
cancer, putting it on the low end of the mutational spectrum. Aside from a previously described heterozygous deletion on chromosome 19 that encodes for a functional, chimeric
protein, there were no other recurrent structural variations that contribute to the
tumor genotype. The lack of a second-hit mutation in the genomic landscape of
fibrolamellar hepatocellular carcinoma makes the DNAJB1-PRKACA fusion
protein the best target for diagnostic and therapeutic advancements. The mutations, altered pathways and structural variants that characterized
fibrolamellar hepatocellular carcinoma were distinct from those in
hepatocellular carcinoma, further defining it as a distinct
carcinoma.