Detection of structural variations during liver cancer progression

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world and accounts for the vast majority of all liver cancers. HCC develops in response to various factors including viral infections, aflatoxin, alcohol and metabolic diseases. Recent studies have highlighted substantial differences in the acquired genomic alterations depending on the causative agent. Despite such a mutagen-dependent genetic heterogeneity, HCC is almost invariably associated with an underlying inflammatory state, whose direct contribution to the acquisition of critical genomic changes is not yet clear. The aim of my PhD project has been to understand how chronic inflammation and fibrosis affect the cancer genome. We mapped the acquired genomic alterations in human and mouse HCCs induced by defects in hepatocyte biliary transporters. These HCCs arise as a result of chronic exposure to non-neutralized bile acids that cause the onset of chronic inflammation and develop into cancer in the absence of exogenous direct (viruses) or indirect (alcohol) mutagens. We first studied the mutational landscapes of human and mouse cancer genomes and found a surprisingly low number of somatic point mutations with no impairment of cancer genes. We next studied the acquisition of somatic copy number variations (CNVs) and used well-established approaches for detecting CNVs from SNP arrays and whole genome sequencing data. We also developed a novel method, GeneCNV, for the identification of CNVs from targeted re-sequencing screenings. Overall, we observed the acquisition of massive gene copy number gains and rearrangements in both human and mouse HCCs. Amplifications preferentially occurred at late stages of cancer development and frequently targeted the mitogen-activated protein kinase (MAPK) signalling pathway, in particular, direct regulators of c-Jun NH2-terminal kinases (JNKs). We showed that that pharmacological inhibition of JNK impairs the adenoma-to- carcinoma progression in mouse. This suggests that JNK inhibition may be a useful therapeutic approach to block HCC onset in bile salt export pump (BSEP) deficiency patients waiting for liver transplantation. Altogether, this study showed that human BSEP-HCCs and mouse Mdr2-KO HCCs acquire a similar genomic signature, thus highlighting the remarkable analogy between human and mouse tumours with similar etiopathogenesis. This genomic signature differs from that of other HCCs profiled so far, which were for the most part virus induced. This demonstrates that HCC in the absence of external agents develops through genomic alterations that can be clearly distinguished from those determined by other etiological factors.