EGFR, PIK3CA, KRAS and BRAF mutations in meningiomas

Abstract

Meningiomas are among the most frequent intracranial tumors. Treatment involves surgical resection with optional subsequent radiotherapy for high-grade meningiomas or radiosurgery following incomplete tumor removal. At present, no pharmacological agents are used as treatment. The use of targeted therapies has been considered, and specific therapies, including anti-EGFR treatment, have been clinically tested. The experience from the treatment of various types of cancers shows that patient outcome depends on the mutational status of particular molecules, including epithelial growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA). Therefore, the aim of the present study was to assess the occurrence and potential use of these markers in patients with meningioma. In total, 55 formalin-fixed, paraffin-embedded meningioma samples were subjected to genomic sequencing of EGFR (exons 18–21), KRAS (exon 1), BRAF (exon 15) and PI3K (exons 9, 20). No mutations were identified in EGFR, KRAS or BRAF. Point mutations in PIK3CA were revealed in the samples of two patients with atypical and anaplastic meningiomas. Although these mutations appear to be rare, this result, along with previously reported findings, indicates that the PI3K/protein kinase B pathway may serve as a more reasonable molecular target for meningioma than EGFR.

Primary Meningeal Pleomorphic Xanthoastrocytoma With Anaplastic Features: A Report of 2 Cases, One WithBRAFV600EMutation and Clinical Response to theBRAFInhibitor Dabrafenib

“…Meningiomas, including recurrent meningiomas, have been found to be BRAF V600E -negative in 3 large series (28, 32, 33). Rhabdoid and other unusual meningiomas have rarely been reported to express GFAP by immunohistochemistry (34–36).…”

Identification of PD-L2, B7-H3 and CTLA-4 immune checkpoint proteins in genetic subtypes of meningioma

“…Recent genetic studies have identified mutations that strongly correlate to meningioma subtype, location and growth rate, suggesting molecular characterization as a more reliable biological classifier of meningioma than WHO grading. [8][9][10][11][12][13][14] Approximately 40-60% of all meningioma harbor NF2 deletions and/or point mutations. NF2 and TERT promotor mutations may be found in each grade but are more frequently observed in grade II and III meningioma and linked to poor prognosis.…”

“…Several mutations present in the genes AKT1, PIK3CA, SMO, TRAF7, KLF4 and POLR2A are associated with grade I meningioma and are primarily linked to tumors located at the skull base, a particularly difficult location to achieve complete surgical resection. [8][9][10][11][12][13][14] These mutations are normally found exclusive of NF2 deletions, and collectively referred to as the non-NF2 group which represent~25% of meningiomas. This leaves only~15-20% with an unknown genetic contribution.…”

New drug candidates for treatment of atypical meningiomas: An integrated approach using gene expression signatures for drug repurposing

“…EGFR has been previously identified as a promising therapeutic target in non-small cell lung tumours, with treatment effect linked to point mutations of the tyrosine kinase domain [ 30 ]. EGFR is expressed in 50–80% of meningiomas [ 31 ], and activation of the EGFR signal was shown to stimulate meningioma proliferation in vitro [ 32 ], further suggesting it as a potential treatment target. However in a recent phase II trial consisting of twenty-five patients, EGFR inhibitors gefitinib and erlotinib did not show significant activity against atypical meningioma [ 33 ].…”