Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system
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Maki Morishita1,2,3, Tomoki Muramatsu1, Yumiko Suto4, Momoki Hirai4, Teruaki Konishi5, Shin Hayashi1, Daichi Shigemizu6,7, Tatsuhiko Tsunoda6,7, Keiji Moriyama2,8, Johji Inazawa1,8
1Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
2Department of Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
3Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan
4Biodosimetry Research Team, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan
5Research Development and Support Center, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan
6Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
7Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Japan
8Bioresource Research Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
Johji Inazawa, e-mail: [email protected]
Keywords: cancer, chromothripsis, microbeam, irradiation, DNA damage
Received: December 08, 2015 Accepted: January 24, 2016 Published: February 04, 2016
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.
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