title: Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas.
abstract: BACKGROUND
  Somatic mutations at residue R132 of isocitrate dehydrogenase 1 (IDH1) were recently discovered in gliomas and leukaemia at a high frequency. IDH1 is a metabolic gene, and the R132 mutations create a new enzymatic activity.
  
  
  OBJECTIVE
  To determine whether IDH1 had somatically acquired mutations in thyroid carcinomas.
  
  
  METHODS
  Exons 4 and 6 of IDH1 were sequenced in a large panel of thyroid tumours (n=138) and compared with the patients normal DNA (n=26). We also correlated IDH1 mutations with clinical-pathological data and BRAF and RAS mutational status.
  
  
  RESULTS
  We identified four novel and two previously described non-synonymous variants in thyroid carcinomas, which were absent in benign tumours and paired normal thyroid. Although IDH1 variants occurred at higher frequency in follicular thyroid carcinomas, follicular variant of papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinomas than the observed variants in classical PTC (15/72 vs 3/37), it was not significant (P=0.1). Sequence alignment across several species shows that all IDH1 genetic alterations occurred at evolutionarily conserved residues located within the active site, and therefore, are likely to affect protein function. Unlike other tumours, IDH1 and BRAF or RAS mutations are not mutually exclusive. There was no association between IDH1 mutational status and clinical characteristics.
  
  
  CONCLUSIONS
  IDH1-acquired genetic alterations are highly prevalent in thyroid carcinomas (16%). Our findings not only extend our understanding of the molecular mechanism underlying pathogenesis of thyroid tumours, but also emphasize the biological differences between tumour types. Those tumours with IDH1 mutations might benefit from therapies that exploit this alteration.
authors: Laboratório Bases Genéticas dos Tumores da Tiroide, Disciplinas de Genética e Endocrinologia, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, São Paulo, SP, Brazil.
authors: Jefferson Pessoa
authors: JP
authors: Hemerly
authors: André Uchimura
authors: AU
authors: Bastos
authors: Janete M
authors: JM
authors: Cerutti
mesh_terms: D018249:Adenoma, Oxyphilic / Q000175:diagnosis / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D018276:Carcinoma, Medullary / Q000175:diagnosis / Q000235:genetics; D002291:Carcinoma, Papillary / Q000175:diagnosis / Q000235:genetics; D020134:Catalytic Domain / Q000235:genetics; D002417:Cattle; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004285:Dogs; D019143:Evolution, Molecular; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D016415:Sequence Alignment; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human