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Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumor. It accounts for 1.5% of all cancers in the United States, and up to 6% in the Arab countries, mainly the Gulf. Often, PTC presents as a suspicious nodule that can be palpated or detected by ultrasound guidance. The main modality of diagnosis is fine needle aspiration biopsy (FNAB), and the main modality of treatment is surgery that may be followed by radiotherapy. PTC is considered curable as most of the patients respond to treatment; however recurrence and metastasis do occur. Molecular studies on PTC revealed different genetic aberrations involved in the activation of the MAP Kinase pathway enzymes specifically RET/PTC, BRAF, and Ras where the latter two aberrations were associated with aggressive cases (recurrence, extrathyroidal invasion, nodal and distant metastasis). These aberrations varied with ethnicity, age, environmental conditions, and prognosis. Several studies showed that detection of BRAF in FNAB will guide the surgeon to perform a total thyroidectomy hence helping in achieving better prognosis (Baloch et al., 2004, Cohen et al., 2004, Hayashida et al., 2004, Salvatore et al., 2004, Xing et al., 2009). Additionally tyrosine kinase inhibitors became available; therefore evaluation of these molecular markers is worth considering in therapeutic as well as in diagnostic and in prognostic protocols.
PTC is the most common variant (>85%) of thyroid cancer followed by follicular, anaplastic, and medullary cancer (AnirbanÂ ,09). PTC arises from the follicular epithelial cells. Its etiology was correlated with environmental factors (radiation) and genetic aberrations as well. Molecular studies revealed that these genetic aberrations occur along the MAP Kinase pathway enzymes. They include the RET/PTC rearrangement involved in tumor initiation and are present mainly in microscopic lesions, in pediatrics, or in those with radiation effect (Xing et al., 07; Fagin, 04). The more aggressive PTC includes Ras and BRAF mutations. BRAF mutation affects the activation loop or the P loop of the protein and disrupts their interaction and destabilizes the inactive conformation; this mutation is found only in histologically proven PTC with an incidence that can reach up to 83% depending on the studied cohort group (Xing et al., 05). BRAF mutation was associated with recurrence as well as extrathyroidal invasion, lymph node and distant metastases, and advanced tumor stages. RET/PTC, BRAF and Ras aberrations rarely overlap in the same tumor.
The RAF gene is located on chromosome 7 (7q34) and is clustered in exons 11 and 15. It encodes a serine/threonine protein kinase belonging to the RAF family, and has three isoforms: ARAF, BRAF and CRAF (Xing et al., 05). "RAF Kinase protein is an intracellular component of the MAPK signaling pathway RET/PTCâ†’Rasâ†’Rafâ†’MEK (Mitogen extracellular Kinase) â†’MAPK/ERK (mitogen-activated-protein kinase/extracellular-signal-regulated kinase) , that plays a fundamental role in cell growth, division and proliferation" (Xing M., 2010). It can cause tumorigenesis when aberrantly activated (Xing et al., 07). The T1799A point BRAF mutation is the most common among the 40 identified mutations in the BRAF gene, it accounts for more than 90% of all the mutations found in this gene (Davies H. et al., 02). This mutation had been formerly called T1796A, based on the NCBI GenBank nucleotide sequence NM 004333, which missed a codon (3 nucleotides) in exon 1 of the BRAF gene, with correct version of the NCBI GenBank nucleotide sequence NT 007914 available, the BRAF mutation is now designated T1799A. The BRAF T1799A mutation (formerly designated BRAF T1796) is an Aâ†’T transversion at position 1799 resulting in a valine (V) to glutamine (E) substitution at residue 600 causing a V600E (formerly designated V599E) amino acid change in the BRAF protein product and subsequent constitutive activation of the BRAF kinase (Davies H. et al., 02).
The Epidermal Growth Factor Receptor (EGFR) activates an important pathway that leads to cell proliferation, differentiation, migration/motility, adhesion, protection from apoptosis, enhanced survival and gene transcription. A large body of experimental and clinical work supports the view that EGFR is a relevant target for cancer therapy. The development of selective tyrosine kinase inhibitors has become an important area of drug discovery for the treatment of a variety of solid tumors such as breast, ovarian and colorectal cancers, lung cancer, and carcinoma of the head and neck. However, other genes like KRAS and EGFR are also important and have not been studied in these patients especially among Arab cases. Even though the most important gene involved in thyroid carcinomas is BRAF, which we have extensively described above, we are going to use this research as a pilot for the detection of mutations in other genes like KRAS and EGFR.
An important finding is that the PTC microcarcinoma variant, thought to be a precursor lesion, has an increased incidence for the past decade, thus raising questionable approaches on how aggressively these patients should be treated. BRAF mutation V600E is proven to be present in PTC microcarcinoma with prognostic implications and a high risk for transformation (Xinying Li et al, 2012; E. Rossella et al, 2012).Therefore, BRAF mutation evaluation may provides a preoperative characterization of those patient, and thus avoiding invasive procedures (E. Rossella et al, 2012). Consequently, it can provide a prediction of the development, persistence and recurrence of the disease.
In brief, BRAF V600E mutation is important to include in research in order to distinguish patients who require aggressive treatments from those who can be treated with conventional therapies. In addition, the availability of tyrosine kinase inhibitors and the valued results in their application to cancers with mutational aberrations leading to tyrosine kinase activation may be a potential therapeutic approach for aggressive tumors. Moreover, the high frequency of PTC in the Arab region specifically the gulf highlights the importance of BRAF mutation evaluation in the Lebanese and Arab populations in study.