The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients

// David G. Darcy 1, 2 , Rachel Chiaroni-Clarke 1 , Jennifer M. Murphy 1, 2 , Joshua N. Honeyman 1, 2 , Umesh Bhanot 3 , Michael P. LaQuaglia 2 , Sanford M. Simon 1 1 Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065, USA 2 Division of Pediatric Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 3 Pathology Core, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA Correspondence to: Sanford M. Simon, e-mail: simon@rockefeller.edu Keywords: Fibrolamellar, hepatocellular carcinoma, cancer, genome, sequencing Received: October 13, 2014 Accepted: November 11, 2014 Published: December 22, 2014 ABSTRACT 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.