title: c-KIT receptor expression is strictly associated with the biological behaviour of thyroid nodules.
abstract: BACKGROUND
  A large amount of information has been collected on the molecular tumorigenesis of thyroid cancer. A low expression of c-KIT gene has been reported during the transformation of normal thyroid epithelium to papillary carcinoma suggesting a possible role of the gene in the differentiation of thyroid tissue rather than in the proliferation. The initial presentation of thyroid carcinoma is through a nodule and the best way nowadays to evaluate it is by fine-needle aspiration (FNA). However many thyroid FNAs are not definitively benign or malignant, yielding an indeterminate or suspicious diagnosis which ranges from 10 to 25% of FNAs. BRAF mutational analysis is commonly used to assess the malignancy of thyroid nodules but unfortunately it still leaves indeterminate diagnoses. The development of molecular initial diagnostic tests for evaluating a thyroid nodule is needed in order to define optimal surgical approach for patients with uncertain diagnosis pre- and intra-operatively.
  
  
  METHODS
  In this study we extracted RNA from 82 FNA smears, 46 malignant and 36 benign at the histology, in order to evaluate by quantitative Real Time PCR the expression levels of c-KIT gene.
  
  
  RESULTS
  We have found a highly preferential decrease rather than increase in transcript of c-KIT in malignant thyroid lesions compared to the benign ones. To explore the diagnostic utility of c-KIT expression in thyroid nodules, its expression values were divided in four arbitrarily defined classes, with class I characterized by the complete silencing of the gene. Class I and IV represented the two most informative groups, with 100% of the samples found malignant or benign respectively. The molecular analysis was proven by ROC (receiver operating characteristic) analysis to be highly specific and sensitive improving the cytological diagnostic accuracy of 15%.
  
  
  CONCLUSIONS
  We propose the use of BRAF test (after uncertain cytological diagnosis) to assess the malignancy of thyroid nodules at first, then the use of the c-KIT expression to ultimately assess the diagnosis of the nodules that otherwise would remain suspicious. The c-KIT expression-based classification is highly accurate and may provide a tool to overcome the difficulties in today's preoperative diagnosis of thyroid suspicious malignancies.
authors.affiliation: Section of Molecular Pathology, Division of Surgical, Molecular, and Ultrastructural Pathology, University of Pisa and Pisa University Hospital, via Roma 57, Pisa, 56100, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tomei
authors.forename: Chiara
authors.initials: C
authors.lastname: Mazzanti
authors.forename: Ivo
authors.initials: I
authors.lastname: Marchetti
authors.forename: Leonardo
authors.initials: L
authors.lastname: Rossi
authors.forename: Katia
authors.initials: K
authors.lastname: Zavaglia
authors.forename: Francesca
authors.initials: F
authors.lastname: Lessi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Apollo
authors.forename: Paolo
authors.initials: P
authors.lastname: Aretini
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Di Coscio
authors.forename: Generoso
authors.initials: G
authors.lastname: Bevilacqua
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D044963:Biopsy, Fine-Needle; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D009154:Mutation / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D012372:ROC Curve; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D016606:Thyroid Nodule / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*
chemical_list: D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf