title: Identification of actionable mutations in malignant pleural mesothelioma.
abstract: BACKGROUND
  Genetic alterations in malignant pleural mesothelioma (MPM) patients are not well-understood.
  
  
  METHODS
  Surgical specimens and tumor biopsies from 42 patients with MPM were collected from 2003 to 2012. The samples were analyzed for mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2 and amplifications in EGFR, MET, PIK3CA, FGFR1, and FGFR2. In addition, 21 patients' samples were analyzed using amplicon-based massively parallel sequencing for actionable mutations in 48 cancer-related genes.
  
  
  RESULTS
  Genetic alterations were detected in 4 patients (one KRAS mutation and 3 PIK3CA amplifications). Patients harboring genetic alterations showed significantly poorer survival than patients with no genetic alterations. Moreover, significance was maintained if the patients only harbored PIK3CA amplification. A total 16 genetic mutations were identified in the 9 patients' samples (4 TP53 mutations, 3 APC mutations, 3 PIK3CA mutations, and 2 VHL mutations, etc.) by deep sequencing.
  
  
  CONCLUSIONS
  Genetic alterations that are potential targets for molecular targeted therapy were detected in MPM. Amplicon-based massively parallel sequencing was shown to have the advantage of more comprehensive genetic analysis. Further investigation in a larger cohort is necessary to uncover more targetable genetic alterations in MPM and to validate their clinical significance.
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan; Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan; Department of Respiratory Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: tshukuya@juntendo.ac.jp.
authors.forename: Takehito
authors.initials: T
authors.lastname: Shukuya
authors.affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Serizawa
authors.affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan; Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, Wakayama 641-8509, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan; Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, Wakayama 641-8509, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Akamatsu
authors.affiliation: Division of Pathology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Abe
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Imai
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tokito
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ono
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Taira
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kenmotsu
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Tateaki
authors.initials: T
authors.lastname: Naito
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Endo
authors.affiliation: Division of Thoracic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Ohde
authors.affiliation: Division of Pathology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan; Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, Wakayama 641-8509, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8777, Japan; Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-shi, Wakayama 641-8509, Japan. Electronic address: ykoh@wakayama-med.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010997:Pleural Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins; C484760:PIK3CA protein, human
keywords: Gene alteration; Gene amplification; Mesothelioma; Mutation; Phosphatidylinositol 3-kinases; VHL tumor suppressor