title: mTOR activation in medullary thyroid carcinoma with RAS mutation.
abstract: OBJECTIVE
  Rearranged during transfection (RET) mutations are well-known genetic events in sporadic and familial medullary thyroid carcinoma (FMTC). The presence of RAS mutations in sporadic cases, challenging the RET paradigm in these tumors, has been recently reported. We intend to evaluate mTOR pathway activation in RET- and RAS-mutated MTC.
  
  
  METHODS
  In this study, we analysed the presence of RET, H-RAS, and K-RAS mutations in a series of 87 MTCs (82 apparently sporadic and five FMTCs; five apparently sporadic MTCs were eventually found to be familial). We also evaluated mTOR activation--using the expression of its downstream effector phospho-S6 ribosomal protein (p-S6) and the expression of the mTOR inhibitor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN)--by immunohistochemistry.
  
  
  RESULTS
  Our results revealed that RET mutations were present in 52.9% of the cases (46/87) and RAS mutations in 12.6% (11/87) of the whole series of MTCs and 14.3% of the 77 sporadic MTCs. The presence of RET and RAS mutations was mutually exclusive. RAS mutations were significantly associated with higher intensity of p-S6 expression (P=0.007), suggesting that the mTOR pathway is activated in such MTCs. We observed also an increased expression of p-S6 in invasive tumors (P=0.042) and in MTCs with lymph node metastases (P=0.046). Cytoplasmic PTEN expression was detected in 58.8% of the cases; cases WT for RAS showed a significantly lower expression of PTEN (P=0.045).
  
  
  CONCLUSIONS
  We confirmed the presence of RAS mutation in 14.3% of sporadic MTCs and report, for the first time, an association between such mutations and the activation of the mTOR pathway. The evaluation of the mTOR activation by pS6 expression may serve as an indicator of invasive MTC.
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Lyra
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Vinagre
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Batista
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: Vasco
authors.initials: V
authors.lastname: Pinto
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Prazeres
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Eloy
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sobrinho-Simões
authors.affiliation: Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal Medical FacultyUniversity of Porto, Al. Prof. Hernâni Monteiro, P-4200 Porto, PortugalInstitute of Molecular Pathology and Immunology of the University of Porto (Ipatimup) - Cancer BiologyRuaDr. Roberto Frias, s/n, 4200-465 Porto, PortugalMolecular Pathology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalEndocrinology Service of the Portuguese Institute of Oncology of Coimbra FGEPE, Av. Bissaya Barreto, 98, 3000-075 Coimbra, PortugalDepartment of PathologyHospital de S. João, Al. Prof. Hernâni Monteiro, P-4200 Porto, Portugal psoares@ipatimup.pt.
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
mesh_terms: D000328:Adult; D000368:Aged; D018278:Carcinoma, Neuroendocrine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C546842:MTOR protein, human; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D058570:TOR Serine-Threonine Kinases