Structure, Dynamics, and Impact of Replication Stress–Induced Structural Variants in Hepatocellular Carcinoma - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Cancer Research Year : 2022

Structure, Dynamics, and Impact of Replication Stress–Induced Structural Variants in Hepatocellular Carcinoma

Quentin Bayard
Camille Péneau
Sandrine Imbeaud
Theo Hirsch
Eric Letouzé

Abstract

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. Significance: 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.
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Dates and versions

inserm-03772189 , version 1 (08-09-2022)

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Quentin Bayard, Pierre Cordier, Camille Péneau, Sandrine Imbeaud, Theo Hirsch, et al.. Structure, Dynamics, and Impact of Replication Stress–Induced Structural Variants in Hepatocellular Carcinoma. Cancer Research, 2022, 82 (8), pp.1470-1481. ⟨10.1158/0008-5472.CAN-21-3665⟩. ⟨inserm-03772189⟩
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