Chromothripsis drives the evolution of gene amplification in cancer.

ABSTRACT: Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes^1-3, and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of

SUBMITTER: Shoshani O 

PROVIDER: S-EPMC7933129 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature