Shruti Sinha

Hepatocellular carcinoma (HCC) is one of the most frequent and lethal cancers and accounts for 70-80% of all liver cancer. HCC is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is unclear. We mapped the acquired genomic alterations in the exome of human and mouse HCCs induced by defects in hepatocyte biliary transporters, which cause the onset of chronic inflammation that develops into cancer even in the absence of external causative agents. In both human and mouse cancer genomes we found few somatic point mutations with no impairment of cancer genes, which is very different from other HCCs studied so far. To identify copy number variations directly from exome sequencing data, we developed a novel method that combines the frequency of heterozygous germline mutations with the read depth to identify genes undergoing deletion, amplification and LOH events. We applied this method to mouse exome re-sequencing data and observed the acquisition of massive gene amplification and rearrangements in both species. Copy number gains preferentially occurred at late stages of cancer development and frequently targeted the MAPK signaling pathway, and in particular direct regulators of JNK. The pharmacological inhibition of JNK retarded cancer progression in the mouse. Our study demonstrates that HCC induced by bile acids and inflammation develops through genomic modifications that can be clearly distinguished from those determined by other etiological factors, such as virus and alcohol.