MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking Journal Article

Authors: Arcila, M. E.; Drilon, A.; Sylvester, B. E.; Lovly, C. M.; Borsu, L.; Reva, B.; Kris, M. G.; Solit, D. B.; Ladanyi, M.
Article Title: MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking
Abstract: 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 AACR.
Keywords: signal transduction; protein kinase b; adult; clinical article; controlled study; human tissue; treatment outcome; aged; human cell; overall survival; somatic mutation; cancer staging; dna damage; disease association; mitogen activated protein kinase kinase 1; mitogen activated protein kinase inhibitor; epidermal growth factor receptor; epidermal growth factor receptor 2; cohort analysis; smoking; information retrieval; age; lung adenocarcinoma; gender; computer model; k ras protein; drug sensitivity; b raf kinase; race; nucleic acid base substitution; phosphatidylinositol 4,5 bisphosphate 3 kinase; human; male; female; priority journal; article
Journal Title: Clinical Cancer Research
Volume: 21
Issue: 8
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2015-04-15
Start Page: 1935
End Page: 1943
Language: English
DOI: 10.1158/1078-0432.ccr-14-2124
PROVIDER: scopus
PMCID: PMC4401580
PUBMED: 25351745
Notes: Export Date: 4 May 2015 -- Source: Scopus
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MSK Authors
  1. David Solit
    431 Solit
  2. Marc Ladanyi
    861 Ladanyi
  3. Boris A Reva
    36 Reva
  4. Maria Eugenia Arcila
    336 Arcila
  5. Mark Kris
    597 Kris
  6. Alexander Edward Drilon
    136 Drilon