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Updated: Apr 21, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking
Maria E Arcila1, Alexander Drilon2, Brooke E Sylvester3
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. arcilam@mskcc.org.
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.
Insights
Rare MEK1 mutations in lung adenocarcinoma (LAD) are linked to smoking. These genetic alterations define a unique cancer subset potentially treatable with MEK inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The MAPK/ERK pathway is frequently altered in lung adenocarcinoma (LAD).
- EGFR, KRAS, and BRAF mutations are common, but MEK1 mutations are rare and poorly understood.
- Identifying distinct molecular subsets is crucial for targeted therapies.
Purpose of the Study:
- To define the molecular characteristics and clinical significance of MEK1 mutations in LAD.
- To determine the frequency and types of MEK1 mutations in a large LAD cohort.
- To investigate the association of MEK1 mutations with patient demographics, smoking status, and treatment outcomes.
Main Methods:
- Targeted sequencing of a large LAD cohort for MEK1 and other key pathway mutations.
- Analysis of public cancer genomic datasets to identify additional MEK1-mutated cases.
- Correlation of MEK1 mutations with clinical data and comparison of overall survival with KRAS- and EGFR-mutant LADs.
Main Results:
- MEK1 mutations were identified in 0.6% of 6,024 LAD cases, predominantly in smokers (97%).
- The most frequent MEK1 mutations were K57N and Q56P, which were mutually exclusive with other driver mutations.
- Smoking-associated G:C>T:A transversions were the predominant mutation type.
Conclusions:
- MEK1 mutations represent a distinct molecular subset of lung cancer, accounting for approximately 1% of cases.
- These mutations are strongly associated with smoking history.
- MEK1-mutated LAD may exhibit sensitivity to MEK inhibitors, suggesting potential therapeutic strategies.
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