MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking.

Arcila ME, Drilon A, Sylvester BE, Lovly CM, Borsu L, Reva B, Kris MG, Solit DB, Ladanyi M
Clin Cancer Res. 2015 21 (8): 1935-43

PMID: 25351745 · PMCID: PMC4401580 · DOI:10.1158/1078-0432.CCR-14-2124

PURPOSE - 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.

EXPERIMENTAL DESIGN - 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.

©2014 American Association for Cancer Research.

MeSH Terms (23)

Adenocarcinoma Adenocarcinoma of Lung Aged Aged, 80 and over Alleles Cell Line DNA Mutational Analysis Exons Female Gene Frequency Genotype Humans Lung Neoplasms Male MAP Kinase Kinase 1 Middle Aged Models, Molecular Mutation Neoplasm Metastasis Neoplasm Staging Prognosis Protein Conformation Smoking

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