PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome

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 IQ: 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 (pS6: 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.