title: Genomic and transcriptional alterations in lung adenocarcinoma in relation to EGFR and KRAS mutation status.
abstract: BACKGROUND
  In lung adenocarcinoma, the mutational spectrum is dominated by EGFR and KRAS mutations. Improved knowledge about genomic and transcriptional alterations in and between mutation-defined subgroups may identify genes involved in disease development or progression.
  
  
  METHODS
  Genomic profiles from 457 adenocarcinomas, including 113 EGFR-mutated, 134 KRAS-mutated and 210 EGFR and KRAS-wild type tumors (EGFRwt/KRASwt), and gene expression profiles from 914 adenocarcinomas, including 309 EGFR-mutated, 192 KRAS-mutated, and 413 EGFRwt/KRASwt tumors, were assembled from different repositories. Genomic and transcriptional differences between the three mutational groups were analyzed by both supervised and unsupervised methods.
  
  
  RESULTS
  EGFR-mutated adenocarcinomas displayed a larger number of copy number alterations and recurrent amplifications, a higher fraction of total loss-of-heterozygosity, higher genomic complexity, and a more distinct expression pattern than EGFR-wild type adenocarcinomas. Several of these differences were also consistent when the three mutational groups were stratified by stage, gender and smoking status. Specific copy number alterations were associated with mutation status, predominantly including regions of gain with the highest frequency in EGFR-mutated tumors. Differential regions included both large and small regions of gain on 1p, 5q34-q35.3, 7p, 7q11.21, 12p12.1, 16p, and 21q, and losses on 6q16.3-q21, 8p, and 9p, with 20-40% frequency differences between the mutational groups. Supervised gene expression analyses identified 96 consistently differentially expressed genes between the mutational groups, and together with unsupervised analyses these analyses highlighted the difficulty in broadly resolving the three mutational groups into distinct transcriptional entities.
  
  
  CONCLUSIONS
  We provide a comprehensive overview of the genomic and transcriptional landscape in lung adenocarcinoma stratified by EGFR and KRAS mutations. Our analyses suggest that the overall genomic and transcriptional landscape of lung adenocarcinoma is affected, but only to a minor extent, by EGFR and KRAS mutation status.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Medicon Village, Lund, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Planck
authors.forename: Karolina
authors.initials: K
authors.lastname: Edlund
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
authors.forename: Sofi
authors.initials: S
authors.lastname: Isaksson
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D056915:DNA Copy Number Variations / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D009154:Mutation; D014158:Transcription, Genetic
chemical_list: D066246:ErbB Receptors