Abstract

BackgroundBRAF is the most frequently mutated gene in differentiated thyroid cancer (DTC). Previous studies on DTC have well documented high rates of the BRAFV600E 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.MethodsA 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.ResultsOverall, 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 BRAFV600E 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).ConclusionsOur 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 BRAFV600E mutation and also suggest a common occurrence of non-hot spot mutations in adult DTC from this highly inbred population.

Highlights

  • BRAF is the most frequently mutated gene in differentiated thyroid cancer (DTC)

  • The hotspot BRAFV600E mutation was found in 95 cases (46.5 %)

  • Lymph node metastasis was more commonly found in 51 tumors (53.7 %) with BRAFV600E mutation compared to 40 tumors (38.1 %) with wild type BRAF (P = 0.038)

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Summary

Introduction

BRAF is the most frequently mutated gene in differentiated thyroid cancer (DTC). The prevalence of hotspot and nonhotspot 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. Thyroid cancer is the most common malignant endocrine tumor. Thyroid cancer usually arises from follicular epithelial cell or parafollicular cells [3]. The latter is the cell of origin of medullary thyroid cancer [3]. Follicular cell-derived thyroid cancer is by far the most common type (95 %) and is classified to differentiated thyroid cancer (DTC), poorly differentiated (PDTC) and undifferentiated (anaplastic) subtypes [3]. Genetic alterations in genes of key cellular signaling pathways, mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways are the main genetic mechanisms of thyroid carcinogenesis [5, 6]

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