title: Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children's Oncology Group.
abstract: Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se(473)) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children's Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 overexpression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival (p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors.
authors.affiliation: Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA. ian.pollack@chp.edu
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Peter C
authors.initials: PC
authors.lastname: Burger
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Marc K
authors.initials: MK
authors.lastname: Rosenblum
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Murdoch
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.forename: Emiko J
authors.initials: EJ
authors.lastname: Holmes
authors.forename: Tianni
authors.initials: T
authors.lastname: Zhou
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Cohen
authors.forename: Regina I
authors.initials: RI
authors.lastname: Jakacki
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002648:Child; D005260:Female; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D058028:Research Report; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human