title: MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking.
abstract: OBJECTIVE
  Genetic alterations affecting the MAPK/ERK pathway are common in lung adenocarcinoma (LAD). Early steps of the signaling pathway are most often affected with EGFR, KRAS, and BRAF mutations encompassing more than 70% of all alterations. Somatic mutations in MEK1, located downstream of BRAF, are rare and remain poorly defined as a distinct molecular subset.
  
  
  METHODS
  Tumors harboring MEK1 mutations were identified through targeted screening of a large LAD cohort concurrently interrogated for recurrent mutations in MEK1, EGFR, KRAS, BRAF, ERBB2/HER2, NRAS, PIK3CA, and AKT. Additional cases were identified through a search of publically available cancer genomic datasets. Mutations were correlated with patient characteristics and treatment outcomes. Overall survival was compared with stage-matched patients with KRAS- and EGFR-mutant LADs.
  
  
  RESULTS
  We identified 36 MEK1-mutated cases among 6,024 LAD (0.6%; 95% confidence interval, 0.42-0.85). The majority of patients were smokers (97%, n = 35/36). There was no association with age, sex, race, or stage. The most common mutations were K57N (64%, 23/36) followed by Q56P (19%, 7/36), all mutually exclusive with other driver mutations in the targeted panel. Transversions G:C>T:A were predominant (89%, 31/35), in keeping with smoking-associated DNA damage. Additional less common somatic mutations were identified in the kinase domain, all of which are predicted to converge into a single interaction area based on in silico 3D modeling.
  
  
  CONCLUSIONS
  MEK1 mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Mutations are predominantly transversions, in keeping with a strong association with smoking.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. arcilam@mskcc.org.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, New York.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Sylvester
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Vanderbilt University School of Medicine, Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Borsu
authors.affiliation: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Boris
authors.initials: B
authors.lastname: Reva
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, New York, New York.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002460:Cell Line; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000401:mortality / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011487:Protein Conformation; D012907:Smoking / Q000009:adverse effects*
chemical_list: D048369:MAP Kinase Kinase 1