Related Experiment Videos
BRAF and RAS mutations in human lung cancer and melanoma
Marcia S Brose1, Patricia Volpe, Michael Feldman
1Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia 19104, USA.
Abstract:
BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10(-7)), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.
Insights
Activating BRAF mutations are common in melanoma but rare in non-small cell lung cancer (NSCLC). These BRAF mutations in NSCLC differ from melanoma, suggesting distinct therapeutic strategies for RAF inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- BRAF mutations drive cell growth and cancer, identified in 66% of melanomas.
- The MAP kinase pathway is frequently activated in non-small cell lung carcinomas (NSCLCs).
Purpose of the Study:
- Investigate BRAF mutations in NSCLC to understand MAP kinase pathway activation.
- Compare BRAF mutation profiles in NSCLC and melanoma to identify potential therapeutic differences.
Main Methods:
- Screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations in exons 11 and 15.
- Analyzed mutation types, including V599 and novel alterations.
Main Results:
- Identified BRAF mutations in 3% of NSCLCs (5 cases) and 63% of melanomas (22 cases).
- Discovered 3 novel BRAF mutations affecting AKT-mediated phosphorylation, suggesting a role in malignant transformation.
- Found significant differences in BRAF mutation patterns between NSCLC (predominantly non-V599) and melanoma (predominantly V599).
Conclusions:
- BRAF mutations are uncommon in NSCLC and distinct from those in melanoma.
- The unique BRAF mutation profile in NSCLC may necessitate different therapeutic approaches with RAF inhibitors.
- BRAF mutations in lung cancer could identify a subset of patients responsive to targeted therapies.