title: Classical V600E and other non-hotspot BRAF mutations in adult differentiated thyroid cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Molecular Endocrinology Section, Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Research Center (MBC 03), PO Box 3354, Riyadh, 11211, Saudi Arabia.
authors.forename: Avaniyapuram Kannan
authors.initials: AK
authors.lastname: Murugan
authors.affiliation: Molecular Endocrinology Section, Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Research Center (MBC 03), PO Box 3354, Riyadh, 11211, Saudi Arabia.
authors.forename: Ebtesam
authors.initials: E
authors.lastname: Qasem
authors.affiliation: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hindi
authors.initials: H
authors.lastname: Al-Hindi
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Molecular Endocrinology Section, Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Research Center (MBC 03), PO Box 3354, Riyadh, 11211, Saudi Arabia. aliz@kfshrc.edu.sa.|Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. aliz@kfshrc.edu.sa.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Alzahrani
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D015995:Prevalence; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; DTC; Mutation; Oncogene; PTC; Saudi Arabia; Thyroid cancer