Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum MeningiomasFunding This work is supported by U.S. NIH 1R21NS099844 (to D. P. Cahill and P. K. Brastianos), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Projektnummer, 401837860 (to Dr. T. Juratli), the Damon Runyon Award (to P. K. Brastianos), Brain Science Foundation (to P. K. Brastianos), and the American Brain Tumor Association (to P. K. Brastianos).
29 August 2018
13 November 2018
10 January 2019 (online)
Objective Posterior fossa meningiomas are surgically challenging tumors that are associated with high morbidity and mortality. We sought to investigate the anatomical distribution of clinically actionable mutations in posterior fossa meningioma to facilitate identifying patients amenable for systemic targeted therapy trials.
Methods Targeted sequencing of clinically targetable AKT1, SMO, and PIK3CA mutations was performed in 61 posterior fossa meningioma using Illumina NextSeq 500 to a target depth of >500 × . Samples were further interrogated for 53 cancer-relevant RNA fusions by the Archer FusionPlex panel to detect gene rearrangements.
Results AKT1 (E17K) mutations were detected in five cases (8.2%), four in the foramen magnum and one in the cerebellopontine angle. In contrast, none of the posterior fossa tumors harbored an SMO (L412F) or a PIK3CA (E545K) mutation. Notably, the majority of foramen magnum meningiomas (4/7, 57%) harbored an AKT1 mutation. In addition, common clinically targetable gene fusions were not detected in any of the cases.
Conclusion A large subset of foramen magnum meningiomas harbor AKT1 E17K mutations and are therefore potentially amenable to targeted medical therapy. Genotyping of foramen magnum meningiomas may enable more therapeutic alternatives and guide their treatment decision process.
Portions of this work were presented at the North American Skull Base Society Annual Meeting, New Orleans, Louisiana, United States, March 4, 2017.
* These authors contributed equally to this work.
- 1 Ostrom QT, Gittleman H, Liao P. , et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro-oncol 2017; 19 (5, suppl_5): v1-v88
- 2 Castellano F, Ruggiero G. Meningiomas of the posterior fossa. Acta Radiol Suppl 1953; 104: 1-177
- 3 Meling TR, Da Broi M, Scheie D, Helseth E. Meningiomas: skull base versus non-skull base. Neurosurg Rev 2018 (e-pub ahead of print). doi:10.1007/s10143-018-0976-7
- 4 Voß KM, Spille DC, Sauerland C. , et al. The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value?. J Neurooncol 2017; 133 (03) 641-651
- 5 Nanda A, Vannemreddy P. Recurrence and outcome in skull base meningiomas: do they differ from other intracranial meningiomas?. Skull Base 2008; 18 (04) 243-252
- 6 Javalkar V, Banerjee AD, Nanda A. Posterior cranial fossa meningiomas. J Neurol Surg B Skull Base 2012; 73 (01) 1-10
- 7 Brastianos PK, Horowitz PM, Santagata S. , et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013; 45 (03) 285-289
- 8 Clark VE, Erson-Omay EZ, Serin A. , et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO . Science 2013; 339 (6123): 1077-1080
- 9 Sahm F, Schrimpf D, Stichel D. , et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 2017; 18 (05) 682-694
- 10 Abedalthagafi M, Bi WL, Aizer AA. , et al. Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro-oncol 2016; 18 (05) 649-655
- 11 Yesilöz Ü, Kirches E, Hartmann C. , et al. Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence. Neuro-oncol 2017; 19 (08) 1088-1096
- 12 Hyman DM, Smyth LM, Donoghue MTA. , et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol 2017; 35 (20) 2251-2259
- 13 Janku F, Wheler JJ, Westin SN. , et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 2012; 30 (08) 777-782
- 14 Janku F, Wheler JJ, Naing A. , et al. PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials. Cancer Res 2013; 73 (01) 276-284
- 15 Strickland MR, Gill CM, Nayyar N. , et al. Targeted sequencing of SMO and AKT1 in anterior skull base meningiomas. J Neurosurg 2017; 127 (02) 438-444
- 16 Sekulic A, Migden MR, Oro AE. , et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366 (23) 2171-2179
- 17 Tang JY, Mackay-Wiggan JM, Aszterbaum M. , et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med 2012; 366 (23) 2180-2188
- 18 Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009; 25 (14) 1754-1760
- 19 Tarasov A, Vilella AJ, Cuppen E, Nijman IJ, Prins P. Sambamba: fast processing of NGS alignment formats. Bioinformatics 2015; 31 (12) 2032-2034
- 20 Li H, Handsaker B, Wysoker A. , et al; 1000 Genome Project Data Processing Subgroup. The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009; 25 (16) 2078-2079
- 21 Ye K, Schulz MH, Long Q, Apweiler R, Ning Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 2009; 25 (21) 2865-2871
- 22 McLaren W, Gil L, Hunt SE. , et al. The Ensembl Variant Effect Predictor. Genome Biol 2016; 17 (01) 122
- 23 Pietrantonio F, Di Nicolantonio F, Schrock AB. , et al. ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer. J Natl Cancer Inst 2017;109(12)
- 24 Zheng Z, Liebers M, Zhelyazkova B. , et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med 2014; 20 (12) 1479-1484
- 25 Bruneau M, George B. Foramen magnum meningiomas: detailed surgical approaches and technical aspects at Lariboisière Hospital and review of the literature. Neurosurg Rev 2008; 31 (01) 19-32 , discussion 32–33
- 26 Agnihotri S, Suppiah S, Tonge PD. , et al. Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas. Nat Commun 2017; 8 (01) 186
- 27 Juratli TA, Thiede C, Koerner MVA. , et al. Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas. Oncotarget 2017; 8 (65) 109228-109237
- 28 Alvarez-Breckenridge C, Miller JJ, Nayyar N. , et al. Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor. NPJ Precis Oncol 2017; 1 (01) 5
- 29 Sahm F, Bissel J, Koelsche C. , et al. AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry. Acta Neuropathol 2013; 126 (05) 757-762
- 30 Rhoton Jr AL. Meningiomas of the cerebellopontine angle and foramen magnum. Neurosurg Clin N Am 1994; 5 (02) 349-377
- 31 Borba LA, de Oliveira JG, Giudicissi-Filho M, Colli BO. Surgical management of foramen magnum meningiomas. Neurosurg Rev 2009; 32 (01) 49-58 , discussion 59–60
- 32 Leon-Ariza DS, Campero A, Romero Chaparro RJ, Prada DG, Vargas Grau G, Rhoton Jr AL. Key aspects in foramen magnum meningiomas: from old neuroanatomical conceptions to current far lateral neurosurgical intervention. World Neurosurg 2017; 106: 477-483
- 33 Juratli TA, McCabe D, Nayyar N. , et al. DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome. Acta Neuropathol 2018; 136 (05) 779-792