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Biomolecules 2015, 5(4), 2464-2476;

Molecular Process Producing Oncogene Fusion in Lung Cancer Cells by Illegitimate Repair of DNA Double-Strand Breaks

Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo 105-8471, Japan
Author to whom correspondence should be addressed.
Academic Editors: Thomas Helleday, Wolf-Dietrich Heyer and Fumio Hanaoka
Received: 30 June 2015 / Revised: 10 September 2015 / Accepted: 14 September 2015 / Published: 30 September 2015
(This article belongs to the Special Issue DNA Damage Response)
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Constitutive activation of oncogenes by fusion to partner genes, caused by chromosome translocation and inversion, is a critical genetic event driving lung carcinogenesis. Fusions of the tyrosine kinase genes ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) occur in 1%–5% of lung adenocarcinomas (LADCs) and their products constitute therapeutic targets for kinase inhibitory drugs. Interestingly, ALK, RET, and ROS1 fusions occur preferentially in LADCs of never- and light-smokers, suggesting that the molecular mechanisms that cause these rearrangements are smoking-independent. In this study, using previously reported next generation LADC genome sequencing data of the breakpoint junction structures of chromosome rearrangements that cause oncogenic fusions in human cancer cells, we employed the structures of breakpoint junctions of ALK, RET, and ROS1 fusions in 41 LADC cases as “traces” to deduce the molecular processes of chromosome rearrangements caused by DNA double-strand breaks (DSBs) and illegitimate joining. We found that gene fusion was produced by illegitimate repair of DSBs at unspecified sites in genomic regions of a few kb through DNA synthesis-dependent or -independent end-joining pathways, according to DSB type. This information will assist in the understanding of how oncogene fusions are generated and which etiological factors trigger them. View Full-Text
Keywords: lung cancer; oncogene; fusion; non-homologous end-joining; synthesis-dependent end-joining lung cancer; oncogene; fusion; non-homologous end-joining; synthesis-dependent end-joining

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Seki, Y.; Mizukami, T.; Kohno, T. Molecular Process Producing Oncogene Fusion in Lung Cancer Cells by Illegitimate Repair of DNA Double-Strand Breaks. Biomolecules 2015, 5, 2464-2476.

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