title: PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome.
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.
authors: Department of Pediatrics, University of California, San Francisco, CA, USA.
authors: Sabine
authors: S
authors: Mueller
authors: Joanna
authors: J
authors: Phillips
authors: Arzu
authors: A
authors: Onar-Thomas
authors: Eloy
authors: E
authors: Romero
authors: Shichun
authors: S
authors: Zheng
authors: John K
authors: JK
authors: Wiencke
authors: Sean M
authors: SM
authors: McBride
authors: Cynthia
authors: C
authors: Cowdrey
authors: Michael D
authors: MD
authors: Prados
authors: William A
authors: WA
authors: Weiss
authors: Mitchel S
authors: MS
authors: Berger
authors: Nalin
authors: N
authors: Gupta
authors: Daphne A
authors: DA
authors: Haas-Kogan
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D060787:Neoplasm Grading; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human