title: Expression and clinical significance of genes frequently mutated in small cell lung cancers defined by whole exome/RNA sequencing.
abstract: 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.
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Reika
authors: R
authors: Iwakawa
authors: 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.
authors: Takashi
authors: T
authors: Kohno
authors: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Yasushi
authors: Y
authors: Totoki
authors: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors: Tatsuhiro
authors: T
authors: Shibata
authors: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104-0045, Japan.
authors: Katsuya
authors: K
authors: Tsuchihara
authors: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104-0045, Japan.
authors: Sachiyo
authors: S
authors: Mimaki
authors: Pathology Division and.
authors: Koji
authors: K
authors: Tsuta
authors: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors: Yoshitaka
authors: Y
authors: Narita
authors: Department of Neuro-Oncology/Neurosurgery, International Medical Center, Saitama Medical University, Saitama 350-1298, Japan.
authors: Ryo
authors: R
authors: Nishikawa
authors: Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
authors: Masayuki
authors: M
authors: Noguchi
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA.
authors: Curtis C
authors: CC
authors: Harris
authors: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4258, USA.
authors: Ana I
authors: AI
authors: Robles
authors: Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors: Rui
authors: R
authors: Yamaguchi
authors: Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors: Seiya
authors: S
authors: Imoto
authors: Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors: Satoru
authors: S
authors: Miyano
authors: Bioinfomatics Group, Research and Development Center, Solution Division 4, Hitachi Government and Public Corporation System Engineering Ltd, Tokyo 135-8633, Japan.
authors: Hirohiko
authors: H
authors: Totsuka
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan and.
authors: Teruhiko
authors: T
authors: Yoshida
authors: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan, Cancer Genome Biology Group, Institute of Predictive and Personalized Medicine of Cancer, 08916 Barcelona, Spain jyokota@ncc.go.jp.
authors: Jun
authors: J
authors: Yokota
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D017423:Sequence Analysis, RNA; D055752:Small Cell Lung Carcinoma / Q000235:genetics*; D013049:Spectrin / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D016160:Retinoblastoma Protein; C580886:TMEM132D protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins; D013049:Spectrin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human