Chromothripsis is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event, rather than an accumulation of a series of subsequent and random alterations.
Chromothripsis occurs commonly in various human
cancers and is thought to be associated with increased
malignancy and
carcinogenesis. However, the causes and consequences of
chromothripsis remain unclear. Therefore, to identify the mechanism underlying the generation of
chromothripsis, we investigated whether
chromothripsis could be artificially induced by ionizing radiation. We first elicited
DNA double-strand breaks in an
oral squamous cell carcinoma cell line HOC313-P and its highly metastatic subline HOC313-LM, using Single Particle Irradiation system to Cell (SPICE), a focused vertical microbeam system designed to irradiate a spot within the nuclei of adhesive cells, and then established irradiated monoclonal sublines from them, respectively. SNP array analysis detected a number of chromosomal copy number alterations (CNAs) in these sublines, and one HOC313-LM-derived monoclonal subline irradiated with 200
protons by the microbeam displayed multiple CNAs involved locally in chromosome 7. Multi-color FISH showed a complex translocation of chromosome 7 involving chromosomes 11 and 12. Furthermore, whole genome sequencing analysis revealed multiple de novo complex chromosomal rearrangements localized in chromosomes 2, 5, 7, and 20, resembling
chromothripsis. These findings suggested that localized ionizing irradiation within the nucleus may induce
chromothripsis-like complex chromosomal alterations via local DNA damage in the nucleus.