Seki Yoshitaka, Mizukami Tatsuji, Kohno Takashi
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.
Biomolecules. 2015 Sep 30;5(4):2464-76. doi: 10.3390/biom5042464.
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.
由染色体易位和倒位导致的癌基因与伙伴基因融合所引起的组成性激活，是驱动肺癌发生的关键遗传事件。酪氨酸激酶基因间变性淋巴瘤激酶（ALK）、原癌基因1（ROS1）或转染重排（RET）的融合发生在1% - 5%的肺腺癌（LADC）中，其产物构成激酶抑制药物的治疗靶点。有趣的是，ALK、RET和ROS1融合优先发生在从不吸烟和轻度吸烟的LADC中，这表明导致这些重排的分子机制与吸烟无关。在本研究中，我们利用先前报道的人类癌细胞中导致致癌融合的染色体重排断点连接结构的下一代LADC基因组测序数据，将41例LADC病例中ALK、RET和ROS1融合的断点连接结构作为“痕迹”，来推断由DNA双链断裂（DSB）和非法连接引起的染色体重排的分子过程。我们发现，根据DSB类型，基因融合是通过DNA合成依赖或非依赖的末端连接途径，在几kb基因组区域的未指定位点对DSB进行非法修复而产生的。这些信息将有助于理解癌基因融合是如何产生的以及哪些病因因素触发了它们。
