PIK3CA alterations in primary (de novo) and secondary glioblastomas

Abstract

We assessed alterations in the EGFR/PTEN/PI3K pathway in 107 primary (de novo) glioblastomas and 32 secondary glioblastomas that progressed from low-grade or anaplastic astrocytomas. SSCP followed by DNA sequencing in exons 9 and 20 of the PIK3CA gene revealed missense mutations in 5/107 (5%) primary and 1/32 (3%) secondary glioblastomas. Quantitative real-time PCR showed PIK3CA amplification (>3 copy numbers) in 14/107 (13%) primary and 3/32 (9%) secondary glioblastomas. Only one glioblastoma showed both PIK3CA mutation and amplification. Taken together with previously published data on EGFR amplification and PTEN mutations, at least one alteration in the EGFR, PTEN, or PIK3CA genes was detected in 63% of primary glioblastomas, which was significantly more frequent than in secondary glioblastomas (31%; P < 0.001). Furthermore, this signaling pathway was altered by either PTEN mutations or PIK3CA amplification in 10 of 12 (83%) malignant glioma cell lines analyzed. These results suggest that the EGFR/PTEN/PI3K pathway is frequently altered in glioblastomas and is a promising target for therapy, in particular for primary glioblastomas.

MicroRNA-451 Inhibits Growth of Human Colorectal Carcinoma Cells via Downregulation of Pi3k/Akt Pathway

“…PI3K regulates the single transmission of AKT phosphorylation. (Gallia et al, 2006, Kita et al, 2007 Several studies show that PI3K inhibition sensitizes glioma cells to radiation and chemical therapy (Opel et al, 2008;Prevo et al, 2008). Modulation of AKT signalling cascade using miRNAs in glioblastoma cell lines was described also in Nan et al In this study, transfection of miR-451 mimicked reduced expression levels of Akt1, Cyclin D1, MMP-2, MMP-9 and Bcl-2.…”

Emerging insights into the molecular and cellular basis of glioblastoma

“…Elevated AKT phosphorylation has been observed in up to 85% of glioblastoma cell lines and patient samples (Wang et al 2004). RTK-independent activation of this pathway in glioblastoma can occur via mutation or amplification of PIK3CA (p110a) (Gallia et al 2006;Kita et al 2007; The Cancer Genome Atlas Research Network 2008), and PIK3CD (p110d) is also overexpressed in some gliomas (Mizoguchi et al 2004). Moreover, the TCGA study revealed recurrent mutations in the gene encoding the p85a regulatory subunit PIK3R1, which likely drive PIK3CA activation through decreased SH2 domain-mediated inhibition (Sun et al 2010).…”

Genetic Profiling: Searching for Novel Genetic Aberrations in Glioblastoma

“…Elevated AKT phosphorylation has been observed in up to 85% of glioblastoma cell lines and patient samples [45]. RTK-independent activation of this pathway in glioblastoma can occur via mutation or amplification of PIK3CA (p110a) [46,47], and PIK3CD (p110d) is also overexpressed in some gliomas [48]. Other amplified regions containing oncogenes, for example AKT3 [22,49] and CCND2 [22,27].…”

“…Mutations in PIK3CA and PIK3R1, coding for the PI3K catalytic subunit p110a and regulatory subunit P85a, have been described [22,23]. RTK-independent activation of this pathway in glioblastoma can occur via mutation of PIK3CA (p110a) [46,47] or through recurrent mutations in the gene encoding the p85a regulatory subunit PIK3R1. This will likely drive PIK3CA activation through decreased SH2 domain-mediated inhibition [87].…”