Rare mutation of PIK3CA in meningiomas

Excerpt

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 p110α 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.

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