title: Ileal neuroendocrine tumors show elevated activation of mammalian target of rapamycin complex.
abstract: BACKGROUND
  Neuroendocrine tumors (NETs) of the ileum are sporadic tumors derived from submucosal gastrointestinal stem cells. They often show clinical symptoms only after hepatic metastasation when curative therapy is limited or impossible. In this study, we analyzed the expression of the candidate genes mammalian target of rapamycin (mTOR), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and death domain-associated protein (DAXX) to investigate the specific oncogenetics and potential therapeutic options for ileal NETs.
  
  
  METHODS
  In a prospective database, all patients who underwent surgical removal of a NET of the ileum between 2001 and 2011 were specified. Expression analysis was performed for mTOR, ATRX, and DAXX by immunohistochemistry of paraffin-embedded tumor samples. To evaluate the results the immunoreactive score was applied. Normal tissue and tumor tissue were analyzed for the comparison of gene expression levels using quantitative-real-time polymerase chain reaction for ATRX and mTOR genes. Results were correlated under pathologic and clinical aspects.
  
  
  RESULTS
  A total of 69 patients were admitted to the study. Positive cytosolic expression of the potential oncogene mTOR was immunohistochemically detected in 76.2% of the human probes. A loss of nuclear ATRX expression was detected in 13.0% of the samples. A nonexpression of the DAXX-protein in cell nuclei was not found (0%). Gene transcript levels did not show a significant alteration in ileal NETs in comparison with normal tissue.
  
  
  CONCLUSIONS
  mTOR is overexpressed in ileal NETs. Additionally, the loss of ATRX expression was registered, thus underlying a tumorigenic role in a subgroup of these tumors. To enable potential therapeutic application of mTOR inhibitors, further trials with larger study groups are needed.
authors.affiliation: Department of Visceral-, Thoracic- and Vascular-Surgery, Philipps-University Marburg, Marburg, Germany; Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Geis
authors.affiliation: Department of Visceral-, Thoracic- and Vascular-Surgery, Philipps-University Marburg, Marburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Fendrich
authors.affiliation: Department of Pathology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Rexin
authors.affiliation: Department of Visceral-, Thoracic- and Vascular-Surgery, Philipps-University Marburg, Marburg, Germany.
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Fazio
authors.affiliation: Department of Visceral-, Thoracic- and Vascular-Surgery, Philipps-University Marburg, Marburg, Germany.
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.affiliation: Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.affiliation: Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Quint
authors.affiliation: Department of Visceral-, Thoracic- and Vascular-Surgery, Philipps-University Marburg, Marburg, Germany. Electronic address: Anna.Heverhagen@med.uni-marburg.de.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Heverhagen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007078:Ileal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007082:Ileum / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D018832:Molecular Chaperones; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ATRX; DAXX; Ileum; Neuroendocrine tumors; mTOR