What are the different types of BRAF (B-Raf proto-oncogene) tumor mutations?

BRAF Tumor Mutations: Classification and Types

BRAF mutations in cancer are classified into three distinct functional classes based on their signaling mechanisms and kinase activity, with the V600E substitution being the most common across multiple tumor types. 1

Class I BRAF Mutations (RAS-Independent Active Monomers)

• V600E is the predominant mutation, accounting for the majority of BRAF alterations in melanoma, papillary thyroid cancer, colorectal cancer, hairy cell leukemia, and ganglioglioma 2
• V600K represents another codon 600 mutation seen in lung cancer and other malignancies 2
• Other codon 600 mutations occur in exon 15 and function similarly to V600E 2
• These mutations signal as RAS-independent constitutively active monomers, leading to continuous MAPK pathway activation regardless of external stimuli 3, 1
• Class I mutations are mutually exclusive of KRAS, EGFR, or ALK alterations 2

Class II BRAF Mutations (RAS-Independent Activated Dimers)

• These mutations function as RAS-independent activated dimers with intermediate to high kinase activity 1
• Include mutations at codons 466 and 469 in exon 11 that are particularly prevalent in lung adenocarcinoma 2
• Exon 11 mutations may coexist with KRAS mutations, unlike V600E alterations 2
• Represent approximately 30% of non-V600 BRAF mutations in certain tumor types 2
• These mutations signal through dimer formation without requiring RAS activation 1

Class III BRAF Mutations (Kinase-Impaired, RAS-Dependent)

• These are kinase-impaired mutations that paradoxically increase MAPK signaling through enhanced RAS binding and subsequent CRAF activation 1
• Represent approximately 70% of non-V600 BRAF mutations in some colorectal cancer cohorts 2
• Class 3 mutations show 50% response rate to anti-EGFR therapy in metastatic colorectal cancer, compared to only 8% for class 2 mutations 2
• Include various point mutations, in-frame insertions, and deletions 4

Additional BRAF Alterations

• Chromosomal rearrangements and gene fusions represent large-scale structural alterations involving BRAF 5, 4
• Unique insertion mutations such as the 599 insertion T mutation have been documented 2
• Non-V600E mutations occur in 2.2% of all metastatic colorectal cancer patients and define a clinically distinct subtype with better prognosis than V600E-mutant disease 2

Prevalence by Cancer Type

• Colorectal cancer: 5-21% harbor BRAF mutations, with majority being V600E 2
• Lung adenocarcinoma: 0.5-4.9% have BRAF mutations, with 50-80% being non-V600E variants 2, 1
• Melanoma: V600E is the predominant mutation 2, 5
• Papillary thyroid carcinoma: Commonly harbors V600E mutations 5

Clinical Testing Implications

• Testing methods must evaluate at minimum exons 11 and 15 to capture both V600E and non-V600E mutations, particularly in lung cancer 2
• Standard melanoma-focused assays often cannot detect exon 11 mutations 2
• VE1 immunohistochemistry detects 90-100% of V600E-mutant adenocarcinomas but has insufficient evidence for routine use in NSCLC 2
• PCR amplification and direct DNA sequencing or allele-specific PCR are acceptable methods for V600E detection 2