title: Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series.
abstract: BACKGROUND
  Approximately 60% of sporadic medullary thyroid carcinomas (sMTC) remain orphan of a recognized genetic cause. Recently, a high percentage of RAS point mutations have been described in RET-negative sMTC. The aim of this study was to assess the prevalence of RAS point mutations in a large series of MTC collected in four Italian centers.
  
  
  METHODS
  For this purpose, we studied codons 12, 13, and 61 of H-, K-, and N-RAS genes in 188 MTC samples, either hereditary or sporadic, by direct sequencing. Correlations between the RAS mutational status and the clinical-pathological features of MTC patients as well as a meta-analysis of all published data were performed.
  
  
  RESULTS
  The prevalence of RAS mutations in the present series of MTC was 10.1%, and 17.6% when considering only RET-negative cases. RAS mutations were found in MTC tumoral tissue, but not in peripheral blood indicating their somatic origin. A novel mutation in codon 72 (M72I) was found, but with a low or null transforming potential. No association was found between the presence of RAS mutations and the clinical-pathological features of the patients. Although not statistically significant, a positive association between the presence of RAS mutations and a better outcome was observed. The meta-analysis of all published studies confirmed a prevalence of 8.8% for RAS mutations in MTC.
  
  
  CONCLUSIONS
  The prevalence of RAS mutations in our MTC series was relatively low and consistent with the meta-analysis data. Only somatic RAS mutations were found and only in RET-negative sMTC. Likewise, MTCs that harbor a RAS mutation identify a subgroup of tumors with less aggressive behavior. To our knowledge, this is the largest series of MTCs studied for the presence of mutations in RAS genes and the first meta-analysis on this specific topic.
authors.affiliation: Department of Endocrinology and Metabolism, University Hospital of Pisa, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ciampi
authors.forename: Caterina
authors.initials: C
authors.lastname: Mian
authors.forename: Laura
authors.initials: L
authors.lastname: Fugazzola
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosci
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.forename: Susi
authors.initials: S
authors.lastname: Barollo
authors.forename: Valentina
authors.initials: V
authors.lastname: Cirello
authors.forename: Valeria
authors.initials: V
authors.lastname: Bottici
authors.forename: Giulia
authors.initials: G
authors.lastname: Marconcini
authors.forename: Pelizzo Maria
authors.initials: PM
authors.lastname: Rosa
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Borrello
authors.forename: Fulvio
authors.initials: F
authors.lastname: Basolo
authors.forename: Clara
authors.initials: C
authors.lastname: Ugolini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Materazzi
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinchera
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D018278:Carcinoma, Neuroendocrine; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D005787:Gene Frequency; D011905:Genes, ras; D006801:Humans; D007558:Italy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins