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MAPK pathway activation in pilocytic astrocytoma.

ABSTRACT: Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions.

SUBMITTER: Jones DT

PROVIDER: S-EPMC3350769 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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MAPK pathway activation in pilocytic astrocytoma.

Jones David T W DT Gronych Jan J Lichter Peter P Witt Olaf O Pfister Stefan M SM

Cellular and molecular life sciences : CMLS 20111213 11

Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA ...[more]

PMID: 22159586

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Project description:Pilocytic astrocytomas occur rarely in adults and show aggressive tumor behavior. However, their underlying molecular-genetic events are largely uncharacterized. Hence, 59 adult pilocytic astrocytoma (APA) cases of classical histology were studied (MIB-1 LI: 1%-5%). Analysis of BRAF alterations using qRT-PCR, confirmed KIAA1549-BRAF fusion in 11 (19%) and BRAF-gain in 2 (3.4%) cases. BRAF-V600E mutation was noted in 1 (1.7%) case by sequencing. FGFR1-mutation and FGFR-TKD duplication were seen in 7/59 (11.9%) and 3/59 (5%) cases, respectively. Overall 36% of APAs harbored BRAF and/or FGFR genetic alterations. Notably, FGFR related genetic alterations were enriched in tumors of supratentorial region (8/25, 32%) as compared with other locations (P = 0.01). The difference in age of cases with FGFR1-mutation (Mean age ± SD: 37.2 ± 15 years) vs. KIAA1549-BRAF fusion (Mean age ± SD: 25.1 ± 4.1 years) was statistically significant (P = 0.03). Combined BRAF and FGFR alterations were identified in 3 (5%) cases. Notably, the cases with more than one genetic alteration were in higher age group (Mean age ± SD: 50 ± 12 years) as compared with cases with single genetic alteration (Mean age ± SD: 29 ± 10; P = 0.003). Immunopositivity of p-MAPK/p-MEK1 was found in all the cases examined. The pS6-immunoreactivity, a marker of mTOR activation was observed in 34/39 (87%) cases. Interestingly, cases with BRAF and/or FGFR related alteration showed significantly lower pS6-immunostatining (3/12; 25%) as compared with those with wild-type BRAF and/or FGFR (16/27; 59%) (P = 0.04). Further, analysis of seven IDH wild-type adult diffuse astrocytomas (DA) showed FGFR related genetic alterations in 43% cases. These and previous results suggest that APAs are genetically similar to IDH wild-type adult DAs. APAs harbor infrequent BRAF alterations but more frequent FGFR alterations as compared with pediatric cases. KIAA1549-BRAF fusion inversely correlates with increasing age whereas FGFR1-mutation associates with older age. Activation of MAPK/ERK/mTOR signaling appears to be an important oncogenic event in APAs and may be underlying event of aggressive tumor behavior. The findings provided a rationale for potential therapeutic advantage of targeting MAPK/ERK/mTOR pathway in APAs.

Project description:BackgroundPilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies for which few recurrent and specific genetic alterations have been identified. In an effort to better understand the molecular biology underlying the pathogenesis of these pediatric brain tumors, we performed higher-order transcriptional network analysis of a large gene expression dataset to identify gene regulatory pathways that are specific to this tumor type, relative to other, more aggressive glial or histologically distinct brain tumours.MethodsRNA derived from frozen human PA tumours was subjected to microarray-based gene expression profiling, using Affymetrix U133Plus2 GeneChip microarrays. This data set was compared to similar data sets previously generated from non-malignant human brain tissue and other brain tumour types, after appropriate normalization.ResultsIn this study, we examined gene expression in 66 PA tumors compared to 15 non-malignant cortical brain tissues, and identified 792 genes that demonstrated consistent differential expression between independent sets of PA and non-malignant specimens. From this entire 792 gene set, we used the previously described PAP tool to assemble a core transcriptional regulatory network composed of 6 transcription factor genes (TFs) and 24 target genes, for a total of 55 interactions. A similar analysis of oligodendroglioma and glioblastoma multiforme (GBM) gene expression data sets identified distinct, but overlapping, networks. Most importantly, comparison of each of the brain tumor type-specific networks revealed a network unique to PA that included repressed expression of ONECUT2, a gene frequently methylated in other tumor types, and 13 other uniquely predicted TF-gene interactions.ConclusionsThese results suggest specific transcriptional pathways that may operate to create the unique molecular phenotype of PA and thus opportunities for corresponding targeted therapeutic intervention. Moreover, this study also demonstrates how integration of gene expression data with TF-gene and TF-TF interaction data is a powerful approach to generating testable hypotheses to better understand cell-type specific genetic programs relevant to cancer.

Dataset Information

MAPK pathway activation in pilocytic astrocytoma.

Publications

MAPK pathway activation in pilocytic astrocytoma.

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