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. 2016 Jul 7;14(1):204.
doi: 10.1186/s12967-016-0958-x.

Classical V600E and other non-hotspot BRAF mutations in adult differentiated thyroid cancer

Avaniyapuram Kannan Murugan  1 , Ebtesam Qasem  1 , Hindi Al-Hindi  2 , Yufei Shi  3 , Ali S Alzahrani  4   5
Affiliations

Classical V600E and other non-hotspot BRAF mutations in adult differentiated thyroid cancer

Avaniyapuram Kannan Murugan et al. J Transl Med. .

Abstract

Background: BRAF is the most frequently mutated gene in differentiated thyroid cancer (DTC). Previous studies on DTC have well documented high rates of the BRAF (V600E) mutation in patients of mixed ages. Previous studies either included a mix of pediatric and adult patients or pediatric patients only. However, the prevalence of hotspot and non-hotspot BRAF mutations and its significance in pure adult DTCs is not yet well determined. In this study we determine the frequency of this classical BRAF mutation and other rare BRAF mutations in pure adult DTCs.

Methods: A total of 204 adult DTC samples (Age >18 years) were analyzed for mutations in exon 15 of the BRAF gene by performing polymerase chain reaction (PCR) amplification of tumor genomic DNAs and direct sequencing of amplicons using Sanger sequencing. Obtained results were correlated to clinical and pathological characteristics of DTCs. Statistical analyses were performed using SPSS (The Statistical Package for Social Sciences) version 20 software.

Results: Overall, BRAF mutations were identified in 48.5 % (99/204) of adult DTCs. Three rare non-hotspot mutations (T599I, T599dup and K601E) were detected in four tumor samples (2 %). One (K601E) of these non-hotspot mutations occurred in conventional papillary thyroid cancer (CPTC) and other three (T599I, T599dup and K601E) were found in follicular variant PTC. We found significant association between BRAF (V600E) mutation and age (P < 0.0001), extrathyroidal invasion (P = 0.017), lymph node metastasis (P = 0.038) and TNM stage III/IV (P = 0.001).

Conclusions: Our study is the first to report BRAF mutations in a pure adult sample of DTCs of Saudi Arabian ethnicity. Our results show a high rate and a strong prognostic role of the classical BRAF (V600E) mutation and also suggest a common occurrence of non-hot spot mutations in adult DTC from this highly inbred population.

Keywords: BRAF; DTC; Mutation; Oncogene; PTC; Saudi Arabia; Thyroid cancer.

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Figures

Fig. 1
Fig. 1
Identification of BRAF mutations in adult differentiated thyroid cancer. a The chromatogram shows a rare, somatic, non-hotspot, insertion mutation of BRAF gene in exon 15 at nucleotide position 1798 [1798insTAC (T599dup)]. b Shows a rare, somatic, non-hotspot, point mutation of BRAF gene in exon 15 at nucleotide position 1796 [C1796T (T599I)]. c A representative sequencing results shows a rare, somatic, non-hot spot, point mutation of BRAF gene in exon 15 at nucleotide position 1801 [A1801G (K601E)] from two independent tumor samples. In all the above cases, sequencing results of the matched normal tissue of each sample are shown in the left side of the panel. All the samples were repeated by independent PCR reactions with forward and reversed sequencing
Fig. 2
Fig. 2
Schematic diagram of the BRAF. a Schematic diagram of the BRAF shows the rare, somatic, non-hot spot, mutations of BRAF gene in exon 15 at various nucleotide positions, numbers in the boxes indicate exons and boxes indicate various domains: RBD-ras binding domain, CRD-cysteine rich domain, KD-kinase domain, L–G loop, a conserved glycine motif. b A diagram of native modeled structure of BRAF homodimer. Each monomer molecule is indicated in different color (red and green). The structure of BRAF protein in complex PDB ID is 4E26. Amino acid residues of rare, non-hotspot, somatic mutation identified in adult differentiated thyroid cancer are plotted in BRAF native protein structure using SWISS PDB viewer and the mutated residues are shown in sphere shape. c Shows the monomer cartoon diagram of native modeled structure of BRAF kinase domain. The structure of BRAF protein kinase domain (monomer) PDB ID is 4WO5. Amino acid residues of rare, non-hotspot, somatic mutation identified in adult differentiated thyroid cancer are plotted in BRAF native protein structure and the molecule is visualized by JSmol
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