Fig. 3: HBV DNA integration mediates interchromosomal genomic rearrangements that lead to megabase-size telomeric deletions in HCC.

a In tumour SA529726, two unrelated HBV-mediated interchromosomal rearrangements between chromosomes 3 and X, and between chromosomes 4 and 7, promote 21.2 Mb and 19.8 Mb telomeric deletions on the 3p and the 4q, respectively. The circos plot (left) represents the translocations (purple lines) revealed by ONT data. Single clusters identified with paired-end mapping data are denoted as triangles (green for positive orientation, purple for negative) on the chromosome ideograms. The copy number profiles are shown in yellow below the chromosome ideograms, with relevant telomeric deletions highlighted in red. The long-read plots (right) represent the alignment of one ONT long-read to chromosomes 3 and X, and chromosomes 4 and 7, of the human reference genome and an HBV consensus sequence, which validates the interchromosomal rearrangements mediated by the virus shown in the circos plot. Here, the analysis of the long-reads supporting the HBV events showed an HBV DNA insertion in a classical fragmented and rearranged form^{5, 17}. The expected configuration of the rearranged chromosome is shown above each long read plot (the ideograms are for illustrative purpose only); ‘v’ denotes the HBV insertion. The long-reads used to construct the long-read plots are annotated in Supplementary Table 1. b Circos plots and chromosome diagrams of similar HBV-mediated non-homologous translocations promoting megabase-size telomeric deletions in four additional HCC tumours. Again, the expected configuration of the rearranged chromosome is shown next to each circos (the ideograms are for illustrative purpose only). In SA501511, three unrelated HBV-mediated translocations involving different loci on chromosome 8 promote huge deletions involving telomeric regions on chromosomes 13q, 4p and 10p. In SA501424, one HBV insertion bridges a genomic translocation between chromosomes 1 and 11 that generates a terminal deletion at 1p. In SA501481 and SA529830, HBV-mediated translocations generate dicentric chromosomes and promote megabase-size terminal deletions.