Clarifying The Biological Significance Of The Chk2 K373e Somatic Mutation Discovered In The Cancer Genome Atlas Database

Identification of somatic mutations that contribute to cancer development leads not only to more precise understanding of cancer pathogenesis, but also development of novel molecular targeted therapies. Analyses of cancer genomes using high-throughput sequencing technology are currently conducted as international collaborative research projects, and the results of those analyses are deposited in public databases, allowing everyone in the world to access to these data. To identify a somatic mutation that plays an important role in cancer pathogenesis, we counted the occurrences of each somatic mutation found in the TCGA lung adenocarcinoma dataset and became interested in the CHK2 K373E mutation (c1117Au003eG), which was present in 31 of 542 patients. The K373E mutation impaired CHK2 autophosphorylation at Thr383 and Ser516. In vitro kinase assay revealed that the K373E mutation markedly attenuates CHK2 kinase activity. Growth curves showed that wild-type CHK2 substantially suppressed cell proliferation, but this effect was lost in the K373E mutant in HCT-15 harboring tetracycline-inducible CHK2. Clonogenic assays revealed that wild-type CHK2 promoted survival after ionizing radiation and this pro-survival function was impaired in K373E CHK2. The results of western blotting and RT-PCR suggested that the p53-independent induction of p21 by CHK2 might underlie these effects. Therefore, we identified a somatic mutation that contributes to cancer pathogenesis, using information in a public database. This kind of attempt is expected to lead to discovering new 9driver9 mutations in the future. Citation Format: Masayoshi Higashiguchi, Izumi Nagatomo, Takashi Kijima, Osamu Morimura, Kotaro Miyake, Toshiyuki Minami, Shohei Koyama, Haruhiko Hirata, Kota Iwahori, Takayuki Takimoto, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh. Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3416. doi:10.1158/1538-7445.AM2017-3416