PIK3CA mutations in glioblastoma multiforme

Abstract

Glioblastoma multiforme WHO grade IV is the most common and malignant variant of astrocytic tumors. Loss of heterozygosity of chromosome 10 and mutations in the tumor suppressor gene PTEN on 10q are molecular hallmarks of glioblastomas. Recently, mutations were identified in PIK3CA, encoding a protein that antagonizes the function of PTEN protein in the PI3K/Akt pathway. To address the question whether an exclusive mutation pattern can be observed in PIK3CA and PTEN, we determined the frequency of mutations in both genes. All coding exons were examined by single strand confirmation polymorphism and direct sequencing. Additionally, we analyzed chromosome 10 for loss of heterozygosity and evaluated the mutational status of TP53. In 70 glioblastomas, 5 (7%) PIK3CA mutations and 10 (14%) PTEN mutations were found. All mutations in PIK3CA located to exons 1, 9 and 20, thereby supporting the concept of mutational hot spot regions. In all but one glioblastoma, mutations were seen either in PIK3CA or in PTEN. In conclusion, the frequency of PIK3CA mutations in glioblastomas appears to be much lower than initially reported.

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

“…In the current study, we investigated 10 exons of PIK3CA, previously shown to harbor mutations, by PCR amplification and direct DNA sequencing and found mutations in 11 of 73 (15%) samples. Several factors, which are discussed below, can account for the disparity between the current study and initial report of PIK3CA mutations in glioblastoma with mutation rates of 15% and 27%, respectively, and numerous other studies (3,(10)(11)(12) reporting a PIK3CA mutation rate of <7%.…”

“…Four additional mutations, G1357A, A3062G, G3129T, and C3139T, although described in other malignancies (2, 6), have not yet been reported in glioblastomas. The remaining mutations in exons 1, 9, and 20 have been described previously in glioblastomas (2,3,10). For each mutated sample, corresponding matched normal DNA, when available, was sequenced to verify that the mutation was somatic.…”

“…In that study, the authors reported PIK3CA mutations in 4 of 15 (27%) glioblastomas. Since that initial report, several additional studies have also investigated glioblastomas for PIK3CA mutations (3,(10)(11)(12) and reported a significantly lower PIK3CA mutation rate (V7%; Table 2 (11) examined all 20 exons of PIK3CA by single-strand conformational polymorphism (SSCP) analysis and direct sequencing of exons 9 and 20; no somatic mutation was found in 30 glioblastomas. Two additional studies examining 20 (10) and 10 (12) exons of PIK3CA by SSCP found mutations in 5 of 70 (7%) and 5 of 97 (5%) samples, respectively.…”

“…Since this initial description, several groups have reported a markedly lower PIK3CA mutation rate ranging from 0% to 7% (3,(10)(11)(12). In addition, there have been no reports of the mutation frequency in pediatric glioblastomas, which may have a different molecular etiology from that of glioblastomas in adult patients.…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…Another study investigating all three genes that encode the catalytic subunits of PI3K (PIK3CA, PIK3CD and PIK3C2B) did not find PIK3CA mutations but did observe PIK3C2B amplification and PIK3CD mRNA overexpression in GBM (Knobbe and Reifenberger, 2003). Interestingly, PIK3CA and PTEN mutations have been observed to occur simultaneously in endometrial tumors and GBM indicating a potential additive effect of both mutations on pathway activation (Broderick et al, 2004;Oda et al, 2005;Hartmann et al, 2005a;Hayes et al, 2006). Intriguingly, 100% (five of five) of GBM with PIK3CA mutation also had 10q LOH (Hartmann et al, 2005a), suggesting the possibility that PTEN may be haploinsufficient when other mutations serve to upregulate signaling through the PI3K pathway, although the small number of tumors involved in this study do not allow a clear conclusion.…”