Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence

Ümmügülsüm Yesilöz; Elmar Kirches; Christian Hartmann; Johannes Scholz; Siegfried Kropf; Felix Sahm; Makoto Nakamura; Christian Mawrin

doi:10.1093/neuonc/nox018

Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence

Neuro Oncol. 2017 Aug 1;19(8):1088-1096. doi: 10.1093/neuonc/nox018.

Authors

Ümmügülsüm Yesilöz¹, Elmar Kirches¹, Christian Hartmann¹, Johannes Scholz¹, Siegfried Kropf¹, Felix Sahm¹, Makoto Nakamura¹, Christian Mawrin¹

Affiliation

¹ Departments of Neuropathology and Biometry and Medical Informatics, Otto-von-Guericke University, Magdeburg,Germany; Departments of Neuropathology and Neurosurgery, Hannover Medical School, Hannover, Germany; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; Department of Neurosurgery, Krankenhaus Köln MerheimKliniken der Stadt Köln gGmbH, University of Witten/Herdecke, Köln, Germany; Center for Behavioural Brain Sciences, Magdeburg,Germany.

Abstract

Background: Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated.

Methods: We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter.

Results: The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho-mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho-extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P < .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found.

Conclusions: AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.

Keywords: AKT1; KLF4; meningioma; skull base.

MeSH terms

Adult
Aged
Aged, 80 and over
Brain Neoplasms / genetics
Brain Neoplasms / metabolism
Female
Humans
Kruppel-Like Factor 4
MAP Kinase Signaling System / genetics
Male
Meningeal Neoplasms / metabolism*
Meningioma / genetics
Meningioma / metabolism*
Meningioma / pathology
Middle Aged
Mutation
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
Skull Base Neoplasms / genetics
Skull Base Neoplasms / metabolism*
TOR Serine-Threonine Kinases / metabolism*
Time Factors

Substances

KLF4 protein, human
Kruppel-Like Factor 4
MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases