Iwakawa Reika, Kohno Takashi, Totoki Yasushi, Shibata Tatsuhiro, Tsuchihara Katsuya, Mimaki Sachiyo, Tsuta Koji, Narita Yoshitaka, Nishikawa Ryo, Noguchi Masayuki, Harris Curtis C, Robles Ana I, Yamaguchi Rui, Imoto Seiya, Miyano Satoru, Totsuka Hirohiko, Yoshida Teruhiko, Yokota Jun
Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan, Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104-0045, Japan.
Carcinogenesis. 2015 Jun;36(6):616-21. doi: 10.1093/carcin/bgv026. Epub 2015 Apr 11.
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. Only 15% of SCLC patients survive beyond 2 years after diagnosis. Therefore, for the improvement of patients' outcome in this disease, it is necessary to identify genetic alterations applicable as therapeutic targets in SCLC cells. The purpose of this study is the identification of genes frequently mutated and expressed in SCLCs that will be targetable for therapy of SCLC patients. Exome sequencing was performed in 28 primary tumors and 16 metastatic tumors from 38 patients with SCLCs. Expression of mutant alleles was verified in 19 cases by RNA sequencing. TP53, RB1 and PTEN were identified as being significantly mutated genes. Additional 36 genes were identified as being frequently (≥10%) mutated in SCLCs by combining the results of this study and two recent studies. Mutated alleles were expressed in 8 of the 36 genes, TMEM132D, SPTA1, VPS13B, CSMD2, ANK2, ASTN1, ASPM and FBN3. In particular, the TMEM132D, SPTA1 and VPS13B genes were commonly mutated in both early and late stage tumors, primary tumors and metastases, and tumors before and after chemotherapy, as in the case of the TP53 and RB1 genes. Therefore, in addition to TP53, RB1 and PTEN, TMEM132D, SPTA1 and VPS13B could be also involved in SCLC development, with the products from their mutated alleles being potential therapeutic targets in SCLC patients.
小细胞肺癌（SCLC）是最具侵袭性的肺癌类型。只有15%的SCLC患者在确诊后能存活超过2年。因此，为改善该疾病患者的预后，有必要识别可作为SCLC细胞治疗靶点的基因改变。本研究的目的是识别在SCLC中频繁突变和表达的基因，这些基因可作为SCLC患者治疗的靶点。对38例SCLC患者的28个原发性肿瘤和16个转移性肿瘤进行了外显子组测序。通过RNA测序在19例中验证了突变等位基因的表达。TP53、RB1和PTEN被确定为显著突变基因。结合本研究结果和两项近期研究，另外36个基因被确定为在SCLC中频繁（≥10%）突变。36个基因中有8个基因的突变等位基因有表达，即跨膜蛋白132D（TMEM132D）、α-辅肌动蛋白1（SPTA1）、VPS13家族成员B（VPS13B）、跨膜蛋白43（CSMD2）、锚蛋白2（ANK2）、ASTN1、异常纺锤体样微管相关蛋白（ASPM）和原纤维蛋白3（FBN3）。特别是，TMEM132D、SPTA1和VPS13B基因在早期和晚期肿瘤、原发性肿瘤和转移瘤以及化疗前后的肿瘤中均有常见突变，与TP53和RB1基因情况相同。因此，除了TP53、RB1和PTEN外，TMEM132D、SPTA1和VPS13B也可能参与SCLC的发生发展，其突变等位基因的产物可能是SCLC患者的潜在治疗靶点。
