The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in diverse cellular processes, such as proliferation, survival, and cytoskeletal rearrangement [reviewed in 9]. Anomalous activation of this pathway has been implicated in the development and progression of a wide variety of human cancers. For instance, inactivation of PTEN, an antagonist of PI3K, is frequently detected in glioblastomas, whereas activation of AKT2, a downstream effector of PI3K, is reported in breast and ovarian tumors. The PI3K/AKT pathway can also be activated by gene amplification and/or overexpression of PIK3CA, which encodes the p110a catalytic subunit of the class IA PI3K [2, 6]. Recently, Samuels et al. reported that somatic mutation is an alternative mechanism for PIK3CA activation and such genetic aberration has been detected in colorectal, gastric, breast, and lung tumors and glioblastomas [8]. About 80% of the base alterations are found clustered in the helical (exon 9) and kinase (exon 20) domains of PIK3CA. In this study, we investigated whether somatic mutation of PIK3CA was involved in meningiomas. Using direct sequencing, we screened for base alterations at the mutational hotspots of PIK3CA, exons 9 and 20, as well as on exon 1, where somatic mutation has been reported in brain tumor [1]. A series of 78 meningiomas (26 grade I, 33 grade II, and 19 grade III), classified according to the current World Health Organization criteria, were examined. Five of these tumors (one grade I, three grade II, and one grade III) were recurrences. Our mutation analysis identified one base substitution, A3140G, with a predicted amino acid change from histidine to arginine at codon 1047 (H1047R) of exon 20 in a primary grade III meningioma (Fig. 1). Such base change was not observed in patient’s peripheral lymphocytes, indicating that it was a somatic alteration. The patient was a 71-year-old female, presented with expressive dysphasia and cognitive dysfunction. Histologic examination of the tumor revealed frank brain invasion, numerous mitoses, and high MIB1 labeling index. The tumor, located in the left temporal lobe, was debulked. The patient died 10 months after initial diagnosis. In addition, our previous methylation analysis indicated that this malignant tumor also had promoter hypermethylation of RB1 [5]. No base alteration on either exon 1 or exon 9 of PIK3CA was detected in the series examined. The H1047R mutation maps to the kinase domain of PIK3CA and the amino acid residue involved is highly conserved through evolution. Previous studies showed that the H1047R mutant protein had elevated kinase activity in vitro [4, 8]. Forced expression of the mutant gene in chicken embryo fibroblasts led to cellular transformation with high efficiency [4]. Moreover, treatment of breast tumor cell lines carrying various PIK3CA mutations, including H1047R, with PI3K inhibitor resulted in decreased proliferation and increased apoptosis [10]. Together these results strongly suggest that the H1047R mutation of PIK3CA is oncogenic. Mawrin et al. recently demonstrated higher levels of activated, phosphorylated Akt in atypical and malignant meningiomas compared with benign tumors [7]. Their results suggest that activation of the PI3K/AKT signaling contributes to the aggressive behavior of malignant meningiomas. Another component of the PI3K/ AKT pathway reported altered in meningiomas is This study was supported by the Research Grant Council of Hong Kong, Hong Kong, China
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