title: New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with doubleRETmutations.
abstract: BACKGROUND
  TheRETproto-oncogene is responsible for the pathogenesis of hereditary (98%) and sporadic (40%) medullary thyroid carcinoma (MTC). In sporadic MTC, somaticRETmutations are associated with a poor prognosis.
  
  
  OBJECTIVE
  We looked at the genetic profile of patients with advanced and metastatic MTC. The correlation between these mutations and outcome was also investigated.
  
  
  METHODS
  70 patients with advanced and metastatic sporadic MTC were studied. Exons 10-11 and 13-16 ofRETwere analysed by direct sequencing. All cases were studied forRASand the majority also forTERTmutations.RET/RAS-negative cases were analysed for other oncogene mutations.
  
  
  RESULTS
  64/70 cases (91.4%) showed a somatic mutation, while 6 (8.6%) were negative. Among the mutated cases,RETmutations, mainly M918T, were the most prevalent (93.8%).K-orH-RASmutations were present in 6.2% of cases and were mutually exclusive withRET.No other mutations were found. Four tumours showed twoRETsomatic mutations. We found a complex somaticRETalteration in 6/60 (10%)RET-positive sporadic MTC cases. A positive correlation between a poor prognosis and the multiple number ofRETmutations was found.
  
  
  CONCLUSIONS
  This study showed a high prevalence of somaticRETmutations in advanced and metastatic MTCs.RASmutations were present in a small percentage of cases and mutually exclusive withRETmutations. In a small number of cases, more than oneRETmutation was present in the same tissue.RETdouble mutations and, to a lesser extent, also complex mutations showed a worse outcome.
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Casella
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Tacito
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bottici
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Valerio
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Viola
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Cappagli
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Matrone
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ciampi
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piaggi
authors.affiliation: Department of Surgical, Medical, Molecular Pathology, University of Pisa, Pisa, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Ugolini
authors.affiliation: Department of Surgical, Medical, Molecular Pathology, University of Pisa, Pisa, Italy.
authors.forename: Liborio
authors.initials: L
authors.lastname: Torregrossa
authors.affiliation: Department of Surgical, Medical, Molecular Pathology, University of Pisa, Pisa, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Basolo
authors.affiliation: Department of Surgical, Medical, Molecular Pathology, University of Pisa, Pisa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Materazzi
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vitti
authors.affiliation: Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
keywords: Cancer: endocrine; medullary thyroid cancer; ras; ret