Bionano Genome Imaging unravels complex structural rearrangements induced by replication stress in liver cancer

Cyclins A2 and E1 regulate the cell cycle by promoting S phase entry and progression. We recently identified a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various mechanisms, including HBV and AAV2 viral insertions, gene fusions and enhancer hijacking. Those poor-prognosis HCCs display a unique signature of structural rearrangements, triggered by replicative stress. This signature is strongly enriched in early-replicated active chromatin regions and is characterized by hundreds of tandem duplications and more complex events called Templated Insertion Cycle (T.I.C.).

 

Structural variation calling from short-read Whole Genome Sequencing provides abnormal junctions by comparing chimeric reads with a reference genome. However, those independent breakpoints are too distant, thus this method is not enough to reconstruct highly complex rearrangements, which may involve up to dozens of regions of the genome linked together. Here we used Bionano data to characterize with certainty large DNA molecules resulting from complex T.I.C.. This analysis allowed us to know which regions of the genome are the acceptor of such complex structural rearrangements. This information is critical in the understanding of how those rearrangements affect genes involved in tumorigenesis by placing oncogenes in different genomic contexts.

 

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