Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma

Elucidating the molecular basis of hepatocellular carcinoma (HCC) is crucial to developing targeted diagnostics and therapies for this deadly disease. The landscape of somatic genomic rearrangements (GRs), which can lead to oncogenic gene fusions, remains poorly characterized in HCC. We have predicted 4314 GRs including large-scale insertions, deletions, inversions and translocations based on the whole-genome sequencing data for 88 primary HCC tumor/non-tumor tissues. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. Albumin (ALB) was found to harbor GRs, deactivating mutations and deletions in 10% of cohort. Integrative analysis identified a pattern of paired intra-chromosomal translocations flanking focal amplifications and asymmetrical patterns of copy number variation flanking breakpoints of translocations. Furthermore, we predicted 260 gene fusions which frequently result in aberrant over-expression of the 3′ genes in tumors and validated 18 gene fusions, including recurrent fusion (2/88) of ABCB11 and LRP2. •We performed WGS of 88 HCC tumor and non-tumor pairs and predicted 4,314 somatic genomic rearrangement events including 260 gene fusions.•We identified chromothripsis affecting 6% of the hepatocellular carcinoma cohort.•We identified a recurrent gene fusion, ABCB11-LRP2, in 2% of the cohort.•We found genomic alterations affecting ALB (serum albumin) in 10% of the cohort.•Our analysis revealed genomic rearrangements as potential causal mechanisms underlying focal amplifications of the CCND1/FGF19 locus.