journal contribution
posted on 2023-03-31, 05:06 authored by Quentin Bayard, Pierre Cordier, Camille Péneau, Sandrine Imbeaud, Theo Z. Hirsch, Victor Renault, Jean-Charles Nault, Jean-Frédéric Blanc, Julien Calderaro, Chantal Desdouets, Jessica Zucman-Rossi, Eric Letouzé Supplementary Figure from Structure, Dynamics, and Impact of Replication Stress–Induced Structural Variants in Hepatocellular Carcinoma
Funding
Réseau national CRB Foie
tumor banks of CHU Bordeaux
French Liver Biobanks network
History
ARTICLE ABSTRACT
Oncogene activation leads to replication stress and promotes genomic instability. Here we combine optical mapping and whole-genome sequencing (WGS) to explore in depth the nature of structural variants (SV) induced by replication stress in cyclin-activated hepatocellular carcinomas (CCN-HCC). In addition to classical tandem duplications, CCN-HCC displayed frequent intra-chromosomal and interchromosomal templated insertion cycles (TIC), likely resulting from template switching events. Template switching preferentially involves active topologically associated domains that are proximal to one another within the 3D genome. Template sizes depend on the type of cyclin activation and are coordinated within each TIC. Replication stress induced continuous accumulation of SVs during CCN-HCC progression, fostering the acquisition of new driver alterations and large-scale copy-number changes at TIC borders. Together, this analysis sheds light on the mechanisms, dynamics, and consequences of SV accumulation in tumors with oncogene-induced replication stress.
Optical mapping and whole-genome sequencing integration unravels a unique signature of replication stress–induced structural variants that drive genomic evolution and the acquisition of driver events in CCN-HCC.
