title: Spectrum of gene mutations detected by next generation exome sequencing in brain metastases of lung adenocarcinoma.
abstract: BACKGROUND
  Brain metastases (BM) are a life-threatening complication. We aimed to analyse gene mutations in lung adenocarcinoma BM.
  
  
  METHODS
  We performed next generation sequencing (NGS) of a pre-defined set of 48 cancer-related genes in a cohort of 76 neurosurgical lung adenocarcinoma BM specimens using a cancer specific gene panel on the MiSeq platform (Illumina, San Diego, CA). NGS results were statistically correlated to patient characteristics. Data on ALK, ROS1, MET and FGFR1 gene status assessed by FISH were available from previous studies in the majority of patients.
  
  
  RESULTS
  Twenty-nine (60.4%) of the 48 investigated cancer-related genes were mutated in at least one BM sample and 64 (84.2%) of the 76 BM samples carried at least one mutated gene. The number of mutated genes per sample ranged from 0 to 9 (median 2). The most commonly mutated genes were TP53, KRAS and CDKN2A, which were affected in 35/76 (46.1%), 29/76 (38.2%) and 17/76 (22.4%) samples, respectively. Other potentially druggable alterations included EGFR mutations (3/76, 3.9% of samples), PIK3CA mutation (2/76, 2.6%), BRAF mutation (1/76, 1.3%) and SMO mutation (1/76, 1.3%). Presence of KRAS mutations was associated with positive smoking history (p=0.015, Chi square test) and presence of EGFR mutation correlated with unfavourable overall survival time from BM diagnosis (p=0.019, log rank test).
  
  
  CONCLUSIONS
  Deleterious gene mutations, some of them with potential therapeutic implications, are found in a high fraction of lung adenocarcinoma BM.
authors.affiliation: Department of Medicine I, Medical University of Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.affiliation: Department of Medicine I, Medical University of Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Berghoff
authors.affiliation: Department of Medicine I, Medical University of Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.
authors.forename: Romina
authors.initials: R
authors.lastname: Koller
authors.affiliation: Department of Medicine I, Medical University of Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.affiliation: Institute of Neurology, Medical University of Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Hainfellner
authors.affiliation: Core facilities, Medical University of Vienna, Vienna, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Liebmann-Reindl
authors.affiliation: Center for Integrative Bioinformatics Vienna (CIBIV), University of Vienna and Medical University of Vienna and Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Niko
authors.initials: N
authors.lastname: Popitsch
authors.affiliation: Immunology Outpatient Clinic, Schwarzspanierstraße 15/1/9, A-1090 Vienna, Austria.
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Geier
authors.affiliation: Core facilities, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria. Electronic address: berthold.streubel@meduniwien.ac.at.
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary* / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary* / Q000601:surgery; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor
keywords: Adenocarcinoma; BRAF mutation; Brain metastases; EGFR mutation; Lung cancer