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

A partir de données portant sur des échantillons tumoraux prélevés sur 6 024 patients atteints d'un adénocarcinome du poumon, cette étude identifie, chez environ 1% des patients, la présence de mutations du gène MEK1, en association avec le tabagisme

Résumé en anglais

Background: 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 over 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 to stage-matched patients with KRAS and EGFR mutant lung adenocarcinomas.

Results: We identified 36 MEK1 mutated cases among 6024 LAD (0.6%, 95% CI 0.42 to 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.

Conclusion: 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.