Abstract

The signaling pathways that underlie the pathogenesis of pediatric gliomas are poorly understood. We characterized the PI3K/Akt/mTOR pathway in pediatric gliomas of all grades. Using immunohistochemistry, we assessed activation of the PI3K/Akt/mTOR pathway by evaluating the downstream signaling molecules phospho(p)-S6, phospho(p)-4BP1, and phospho(p)-PRAS40; PTEN; and PTEN promoter methylation, as well as the MIB labeling index. We correlated these findings with the clinical outcomes of 48 children with gliomas. Eighty percent of high-grade gliomas (12/15) showed activation of the PI3K/Akt/mTOR pathway based on p-S6 and p-4EBP1 expression. The majority of high-grade gliomas were negative for PTEN expression (10/15), and 50% had PTEN promoter methylation (grade III: 2/4; grade IV: 3/6). Low-grade gliomas demonstrated PI3K/Akt/mTOR pathway activation in 14/32 (43.8%) by p-S6 and 16/32 (50%) by p-4EBP1. Over 50% of grade I (6/11) and almost all grade II tumors (6/7) showed PTEN promoter methylation. Tumor grade correlated negatively with PTEN expression and positively with expression of p-S6 and p-4EBP1 (PTEN: P = .0025; pS6: P = .0075; p-4EBP1: P = .0066). There was a trend toward inverse correlation of methylation of the PTEN promoter with expression of PTEN protein (P= .0990) and direct correlation of expression of p-S6 and p-4EBP1 with poorer clinical outcome, as measured by progression-free survival (p-S6: P= .0874; p-4EBP1: P= .0475). Tumors with no PTEN expression had a higher MIB labeling index (P= .007). The majority of pediatric gliomas show activation of the PI3K/Akt/mTOR pathway, with methylation of the PTEN promoter occurring commonly in these tumors.

Links

Publisher Full Text

Authors

Mueller S, Phillips J, Onar-Thomas A, Romero E, Zheng S, Wiencke JK, McBride SM, Cowdrey C, Prados MD, Weiss WA, Berger MS, Gupta N, Haas-Kogan DA

Institution

Department of Pediatrics, University of California, San Francisco, CA, USA.

Source

Neuro-oncology 14:9 2012 Sep pg 1146-52

MeSH

Adolescent
Brain Neoplasms
Child
Child, Preschool
DNA Methylation
DNA, Neoplasm
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Glioma
Humans
Immunoenzyme Techniques
Infant
Infant, Newborn
Male
Neoplasm Grading
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Promoter Regions, Genetic
Proto-Oncogene Proteins c-akt
Real-Time Polymerase Chain Reaction
Signal Transduction
TOR Serine-Threonine Kinases

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22753230