The mTORC1 Complex Is Significantly Overactivated in SDHX-Mutated Paragangliomas

Research output: Contribution to journalAbstract

Authors

  • Lindsey Oudijk
  • Ronald De Krijger
  • Esther Korpershoek
  • Anne Paule Gimenez-Roqueplo
  • Judith Favier
  • Letizia Canu
  • Massimo Mannelli
  • Ida Rapa
  • Maria Currás-Freixes
  • Mercedes Robledo
  • Marcel Smid
  • Mauro Papotti
  • Marco Volante

Colleges, School and Institutes

External organisations

  • Erasmus University Medical Center
  • Reinier de Graaf Hospital - SSDZ
  • INSERM
  • Paris Descartes University
  • Hôpital Européen Georges Pompidou
  • University of Florence
  • University of Torino
  • Carlos III Health Institute Center for Biomedical Research on Rare Diseases

Abstract

Aim: 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.

Conclusion: 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.

Details

Original languageEnglish
Pages (from-to)384-393
Number of pages10
JournalNeuroendocrinology
Volume105
Issue number4
Early online date26 Jan 2017
Publication statusPublished - Nov 2017

Keywords

  • mTOR, Paraganglioma, Pheochromocytoma, Succinate dehydrogenase complex