title: The mTORC1 Complex Is Significantly Overactivated in SDHX-Mutated Paragangliomas.
abstract: OBJECTIVE
  We aimed at exploring the activation pattern of the mTOR pathway in sporadic and hereditary pheochromocytomas (PCCs) and paragangliomas (PGLs).
  
  
  METHODS
  A total of 178 PCCs and 44 PGLs, already characterized for the presence of germline mutations in VHL, RET, NF1, MAX, SDHA, SDHB, SDHC, and SDHD as well as somatic mutations in VHL, RET, H-RAS, and MAX, were included in 5 tissue microarrays and tested using immunohistochemistry for mTOR and Rictor as well as the phosphorylated forms of mTOR, p70S6K, AMPK, AKT, 4EBP1, S6, and Raptor.
  
  
  RESULTS
  The positive correlation among most of the molecules investigated proved the functional activation of the mTOR pathway in PCCs/PGLs. Total mTOR, p-S6K and p-S6, and mTORC1-associated molecules p-Raptor and p-AMPK were all significantly overexpressed in PGLs rather than in PCCs, and in the head and neck rather than in abdominal locations. None of the markers, except for the low expression of p-mTOR, was associated with malignancy. Cluster 1 PCCs/PGLs had higher total mTOR, p-Raptor, and p-S6 expression than cluster 2 PCCs/PGLs. In contrast, p-mTOR and mTORC2-associated molecule Rictor were significantly overexpressed in cluster 2 tumors. Within cluster 1, molecules active in the mTORC1 complex were significantly overexpressed in SDHX- as compared to VHL-mutated tumors.
  
  
  CONCLUSIONS
  In summary, the mTOR pathway is activated in a high proportion of PCCs/PGLs, with a preferential overactivation of the mTORC1 complex in PGLs of the head and neck and/or harboring SDHX mutations.
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.forename: Thomas
authors.initials: T
authors.lastname: Papathomas
authors.forename: Ronald
authors.initials: R
authors.lastname: de Krijger
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.forename: Letizia
authors.initials: L
authors.lastname: Canu
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.forename: Ida
authors.initials: I
authors.lastname: Rapa
authors.forename: Maria
authors.initials: M
authors.lastname: Currás-Freixes
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D005060:Europe; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism*; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013223:Statistics as Topic; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis; D055815:Young Adult
chemical_list: D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Paraganglioma; Pheochromocytoma; Succinate dehydrogenase complex; mTOR