title: Driver Gene and Novel Mutations in Asbestos-Exposed Lung   Adenocarcinoma and Malignant Mesothelioma Detected   by Exome Sequencing.
abstract: BACKGROUND
  Asbestos is a carcinogen linked to malignant mesothelioma (MM) and lung cancer. Some gene aberrations related to asbestos exposure are recognized, but many associated mutations remain obscure. We performed exome sequencing to determine the association of previously known mutations (driver gene mutations) with asbestos and to identify novel mutations related to asbestos exposure in lung adenocarcinoma (LAC) and MM.
  
  
  METHODS
  Exome sequencing was performed on DNA from 47 tumor tissues of MM (21) and LAC (26) patients, 27 of whom had been asbestos-exposed (18 MM, 9 LAC). In addition, 9 normal lung/blood samples of LAC were sequenced. Novel mutations identified from exome data were validated by amplicon-based deep sequencing. Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM.
  
  
  RESULTS
  In asbestos-exposed MM patients, previously non-described NF2 frameshift mutation (one) and BAP1 mutations (four) were detected. Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1. BAP1 and COPG1 mutations were seen exclusively in MM. Pathogenic KRAS mutations were common in LAC patients (42 %), both in non-exposed (n = 5) and exposed patients (n = 6). Pathogenic BRAF mutations were found in two LACs.
  
  
  CONCLUSIONS
  BAP1 mutations occurred in asbestos-exposed MM. MRPL1, SDK1, SEMA5B, and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure. KRAS mutations in LAC were not associated with asbestos exposure.
authors.forename: Satu
authors.initials: S
authors.lastname: Mäki-Nevala
authors.forename: Virinder Kaur
authors.initials: VK
authors.lastname: Sarhadi
authors.forename: Aija
authors.initials: A
authors.lastname: Knuuttila
authors.forename: Ilari
authors.initials: I
authors.lastname: Scheinin
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Sonja
authors.initials: S
authors.lastname: Lagström
authors.forename: Mikko
authors.initials: M
authors.lastname: Rönty
authors.forename: Eeva
authors.initials: E
authors.lastname: Kettunen
authors.forename: Kirsti
authors.initials: K
authors.lastname: Husgafvel-Pursiainen
authors.forename: Henrik
authors.initials: H
authors.lastname: Wolff
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D001194:Asbestos / Q000009:adverse effects; D015815:Cell Adhesion Molecules / Q000235:genetics; D020756:Coatomer Protein / Q000235:genetics; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008654:Mesothelioma / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D024101:Mitochondrial Proteins / Q000235:genetics; D010453:Peptide Synthases / Q000235:genetics; D010534:Peritoneal Neoplasms / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D010997:Pleural Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D036081:Receptors, Eph Family / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics; D039961:Semaphorins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; C000612051:COPG1 protein, human; D015815:Cell Adhesion Molecules; D020756:Coatomer Protein; C117307:KRAS protein, human; C000612050:MRPL1 protein, human; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; C493091:SDK1 protein, human; C409766:SEMA3B protein, human; D039961:Semaphorins; D025521:Tumor Suppressor Proteins; D001194:Asbestos; C512478:EGFR protein, human; D066246:ErbB Receptors; D036081:Receptors, Eph Family; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D043222:Ubiquitin Thiolesterase; D016283:Proto-Oncogene Proteins p21(ras); D010453:Peptide Synthases; C510505:TTLL6 protein, human