It was determined that 5 lung adenocarcinoma oncogens are mutually exclusive and present in more than 50% of adenocarcinoma cases. The oncogenes include KRAS, EGFR, ALK, ERBB2, and BRAF. KRAS mutations are the most common ones; it is responsible for encoding GTPase that is able to send signals when GTP bound through RAF and ERK (Greulich, 2011; Jackman, Miller, Cioffredi, et al., 2009). Mutations that occur cause decrease in GTPase activity and enhanced GTP-bound protein, which leads to boost of mitogenic signalling via RAF.
EGFR activation encourages protein tyrosine kinase and mutations were identified in 3 kinase domain exons that encode G719S or G719C in exon 18, small fragments in 19 and L858R or L861Q in 21 (Jackman, Miller, Cioffredi, et al., 2009). Mutations in 20 exons appeared not to be sensitive to gefitinib or erlotinib and became the class of primary resistance alterations. ALK mutations obtain 4% frequency and are associated with abnormal cell proliferation and adenocarcinomas. The most frequent ones are EML4-ALK and patients with it are much younger than majority of other patients (Greulich, 2011). EGRBB2 mutations are small in-frame inclusion in exon 20 of the kinase domain. BRAF mutations take place in exons 11 and 15, however they are rather rare in lung adenocarcinoma.
Other oncogenes that were exposed to have lung cancer related mutations include: PIK3CA with 1-2% alteration frequency and cluster of mutations in the helical and kinase domains; and NRAS with Q61L mutation, as well as alterations at codons of 12 and 61 (Greulich, 2011).
Greulich, H. (2011). The Geomics of Lung Adenocarcinoma: Opportunities for Targeted Therapies. Gene and Cancer 1(12):1200-12010.
Jackman, D. M., Miller, V. A., Cioffredi, L. D. et al. (2009). Impact of Epidermal Growth Factor Receptor and KRAS Mutations on Clinical Outcomes in Previously Untreated Non-Small Cell Lung Cancer Patients: Results of an online Tumor Registry of Clinical Trials. Clin Cancer Res 15:5267-5273.
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Posted by: Roseanne Lohmann