Assessment of BRAF V600E (VE1) protein expression and BRAF gene mutation status in codon 600 in benign and malignant salivary gland neoplasms

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Salivary gland tumors are uncommon, and one of the most heterogeneous group of malignancies. Malignant salivary gland neoplasms account for less than 0.5% of all malignancies worldwide, and approximately 3–5% of all head‐and‐neck cancers 1. According to the clinical follow‐up, the main prognostic parameters for salivary gland cancers are clinical stage and tumor size. However, studies have emphasized the role of several oncogenes, growth factors, and growth factor‐binding receptors as being important factors in the initiation and/or progression of salivary gland tumors 3.
The evaluation of cancer cell signaling pathways and new genetic aberrations may lead to new insights into clinical outcomes, and offer new therapeutic strategies. The mitogen‐activated protein kinase (MAPK) pathway, which contains the RAS/RAF/MEK/ERK pathway is an evolutionarily conserved kinase signaling pathway that includes cascades playing significant roles in cellular and tissue functions, including tumor growth, differentiation, proliferation, angiogenesis, and the formation of both local lymph node and distant metastases and is one of the most commonly dysregulated pathways in human cancers 4. The RAF family members are three highly conserved serine/threonine kinases (A‐RAF, B‐RAF, and C‐RAF or RAF‐1) activated by a series of complex events including their recruitment to the plasma membrane mediated by an interaction with RAS, dimerization of RAF proteins and phosphorylation on different domains 5. Mutations in the BRAF gene have been found in approximately 8% of all solid tumors 4. Among BRAF mutations, over 90% are in codon 600, and among these, over 90% are a single nucleotide mutation resulting in the substitution of glutamic acid for valine (BRAF V600E: nucleotide 1799 T>A; codon GTG>GAG). Other common BRAF mutations in codon 600 are BRAF V600E2, V600D, V600K, V600R, and V600M6. BRAF V600E mutations are detected in 100% of hairy cell leukemias, 40–60% of malignant melanomas, approximately 45% of papillary thyroid carcinomas, approximately 5–15% of colorectal adenocarcinomas, 35% of serous low‐grade and borderline ovarian carcinomas, 1–3% of non‐small cell lung carcinoma, 60% of pleomorphic xanthoastrocytoma, gangliogliomas, 38% of Langerhans cell histiocytosis, and in 54% of cases of Erdheim–Chester disease 7. Thus, the availability of highly specific and sensitive diagnostic tests, allowing for the rapid detection of mutant protein, as well as for the mutation status of selected MAPK signaling pathway kinases, is fundamental in the implementation of targeted therapeutic strategies.
Mutations of the BRAF gene in salivary gland tumors are described rarely, and their role remains unclear. Thus, the aim of this study was to analyze BRAF V600E (VE1) protein expression and BRAF V600 mutation status in salivary gland cancers.

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