title: VEGF, VEGFR3, and PDGFRB protein expression is influenced by RAS mutations in medullary thyroid carcinoma.
abstract: BACKGROUND
  Tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical results in medullary thyroid carcinoma (MTC) patients. However, the considerable variability in patient response to treatment with TKIs remains largely unexplained. There is evidence that it could be due, at least in part, to alterations in genes associated with the disease via their effect on the expression of TKI targets. The objective of this study was to evaluate the influence of RAS mutations on the expression levels in MTC tumors of eight key TKI target proteins.
  
  
  METHODS
  We assessed by immunohistochemistry the expression of EGFR, KIT, MET, PDGFRB, VEGF, VEGFR1, VEGFR2, and VEGFR3 in a series of 84 primary MTC tumors that had previously been molecularly characterized, including 14 RAS-positive, 18 RET(M918T)-positive, and 24 RET(C634)-positive tumors, as well as 15 wild-type tumors with no mutations in the RET or RAS genes.
  
  
  RESULTS
  In contrast to RET-positive tumors, RAS-positive tumors expressed neither PDGFRB nor MET (p=0.0060 and 0.047, respectively). Similarly, fewer RAS-positive than RET-related tumors expressed VEGFR3 (p=0.00062). Finally, wild-type tumors expressed VEGF more often than both RAS- and RET-positive tumors (p=0.0082 and 0.011, respectively).
  
  
  CONCLUSIONS
  This is the first study identifying that the expression of TKI targets differs according to the presence of RAS mutations in MTC. This information could potentially be used to select the most beneficial TKI treatment for these patients.
authors.affiliation: 1 Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre , Madrid, Spain .
authors.forename: Veronika
authors.initials: V
authors.lastname: Mancikova
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Maria
authors.initials: M
authors.lastname: Curras-Freixes
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Gómez
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: Iris
authors.initials: I
authors.lastname: Kersten
authors.forename: Luis Javier
authors.initials: LJ
authors.lastname: Leandro-García
authors.forename: Iñaki
authors.initials: I
authors.lastname: Comino-Méndez
authors.forename: María
authors.initials: M
authors.lastname: Apellaniz-Ruiz
authors.forename: Lara
authors.initials: L
authors.lastname: Sánchez
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
authors.forename: Julia
authors.initials: J
authors.lastname: Sastre-Marcos
authors.forename: Juan F
authors.initials: JF
authors.lastname: García
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D018278:Carcinoma, Neuroendocrine; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C581309:FLT4 protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; D040321:Vascular Endothelial Growth Factor Receptor-3; D018631:ras Proteins