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. 2016 May;18(5):649-55.
doi: 10.1093/neuonc/nov316. Epub 2016 Jan 28.

Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma

Malak Abedalthagafi  1 , Wenya Linda Bi  1 , Ayal A Aizer  1 , Parker H Merrill  1 , Ryan Brewster  1 , Pankaj K Agarwalla  1 , Marc L Listewnik  1 , Dora Dias-Santagata  1 , Aaron R Thorner  1 , Paul Van Hummelen  1 , Priscilla K Brastianos  1 , David A Reardon  1 , Patrick Y Wen  1 , Ossama Al-Mefty  1 , Shakti H Ramkissoon  1 , Rebecca D Folkerth  1 , Keith L Ligon  1 , Azra H Ligon  1 , Brian M Alexander  1 , Ian F Dunn  1 , Rameen Beroukhim  1 , Sandro Santagata  1
Affiliations

Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma

Malak Abedalthagafi et al. Neuro Oncol. 2016 May.

Abstract

Background: Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define.

Methods: We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7.

Results: Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base.

Conclusion: This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

Keywords: AKT1; NF2; PIK3CA; SMO; aCGH; meningioma; molecular pathology.

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Figures

Fig. 1.
Fig. 1.
Mutation and copy number profiling of a clinical cohort of meningiomas. Data are shown for all 150 patient samples for which both copy number alterations and exome sequencing of target genes were available. The top panel displays patient demographics. The second panel displays clinical and pathologic information. The third panel shows mutation status, and the bottom panel shows copy number alterations. The cytogenetic abnormality score (CAS) is plotted in the bottom row. Dark grey symbols denote samples with unavailable data. The data used to generate these plots and an additional, sortable table are available in Supplementary material, Tables S1 and S2, respectively. Supplementary material, Table S2 contains numerical values for age (y), mitoses (per 10 high-power fields), and cytogenetic abnormality score (CAS).
Fig. 2.
Fig. 2.
Diagrams summarizing mutation analysis. (A) Schematic diagram of PI3K protein encoded by the PIK3CA gene and indicating the location of missense mutations and deletions relative to defined functional domains. (p85, PI3K p85 regulatory subunit binding domain; RBD, Ras-binding domain; C2, calcium-dependent phospholipid-binding domain; Helical, PI3K helical domain; Kinase, PI3/PI4 kinase domain). (B) Schematic diagram depicting the approximate location of PIK3CA, SMO, AKT1, and TRAF7/KLF4-mutant meningiomas in the skull base. (C) Venn diagram showing the relationship of mutations in NF2, TRAF7, SMO (L412F and W535L), AKT1 (E17K), KLF4 (K409Q), and PIK3CA. The circle labeled “other” represents meningiomas in which we did not detect a mutation in the 6 genes evaluated in this study. The asterisks indicate that one PIK3CA mutant-meningioma harbored a KLF4 mutation, which is not illustrated in figure 2C.
See this image and copyright information in PMC

Comment in

  • PIK3CA mutations in meningioma.
    Zadeh G, Karimi S, Aldape KD. Zadeh G, et al. Neuro Oncol. 2016 May;18(5):603-4. doi: 10.1093/neuonc/now029. Neuro Oncol. 2016. PMID: 27257280 Free PMC article. No abstract available.
  • Targeted sequencing of SMO and AKT1 in anterior skull base meningiomas.
    Strickland MR, Gill CM, Nayyar N, D'Andrea MR, Thiede C, Juratli TA, Schackert G, Borger DR, Santagata S, Frosch MP, Cahill DP, Brastianos PK, Barker FG 2nd. Strickland MR, et al. J Neurosurg. 2017 Aug;127(2):438-444. doi: 10.3171/2016.8.JNS161076. Epub 2016 Nov 25. J Neurosurg. 2017. PMID: 27885953

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