title: KRAS-G12C mutation is associated with poor outcome in surgically resected lung adenocarcinoma.
abstract: BACKGROUND
  The aim of this study was to examine the effects of KRAS mutant subtypes on the outcome of patients with resected lung adenocarcinoma (AC).
  
  
  METHODS
  Using clinical and sequencing data, we identified 179 patients with resected lung AC for whom KRAS mutational status was determined. A multivariate Cox model was used to identify factors associated with disease-free survival (DFS) and overall survival (OS). Publicly available mutation and gene-expression data from lung cancer cell lines and lung AC were used to assess whether distinct KRAS mutant variants have a different profile.
  
  
  RESULTS
  Patients with KRAS mutation had a significantly shorter DFS compared with those with KRAS wild-type (p = 0.009). Patients with KRAS-G12C mutant tumors had significantly shorter DFS compared with other KRAS mutants and KRAS wild-type tumors (p < 0.001). In the multivariate Cox model, KRAS-G12C remained as an independent prognostic marker for DFS (Hazard ratio = 2.46, 95% confidence interval 1.51-4.00, p < 0.001) and for OS (Hazard ratio = 2.35, 95% confidence interval 1.35-4.10, p = 0.003). No genes were statistically significant when comparing the mutational or transcriptional profile of lung cancer cell lines and lung AC harboring KRAS-G12C with other KRAS mutant subtypes. Gene set enrichment analysis revealed that KRAS-G12C mutants overexpressed epithelial to mesenchymal transition genes and expressed lower levels of genes predicting KRAS dependency.
  
  
  CONCLUSIONS
  KRAS-G12C mutation is associated with worse DFS and OS in resected lung AC. Gene-expression profiles in lung cancer cell lines and surgically resected lung AC revealed that KRAS-G12C mutants had an epithelial to mesenchymal transition and a KRAS-independent phenotype.
authors.affiliation: *Thoracic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan; †Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor, Michigan; ‡Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; §Department of Biostatistics, University of Michigan, Ann Arbor, Michigan; ‖Veterans Administration Medical Center, Ann Arbor, Michigan; ¶Translational Research Laboratory, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain; and #Department of Medical Oncology, Thoracic Oncology Multidisciplinary Unit, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Nadal
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.forename: Hiroe
authors.initials: H
authors.lastname: Shiratsuchi
authors.forename: Christine
authors.initials: C
authors.lastname: Sam
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Kalemkerian
authors.forename: Dean
authors.initials: D
authors.lastname: Brenner
authors.forename: Jules
authors.initials: J
authors.lastname: Lin
authors.forename: Rishindra M
authors.initials: RM
authors.lastname: Reddy
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chang
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellà
authors.forename: Felipe
authors.initials: F
authors.lastname: Cardenal
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Nithya
authors.initials: N
authors.lastname: Ramnath
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000601:surgery*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins