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Modeling Astrocytoma Pathogenesis In Vitro and In Vivo Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice
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Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas

Joshua D Schiffman1, J Graeme Hodgson, Scott R VandenBerg

  • 1Divison of Pediatric Hematology/Oncology and Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA.

Cancer Research
|January 14, 2010
PubMed

Insights

This study identifies distinct BRAF gene alterations in pediatric astrocytomas. KIAA1549-BRAF fusions characterize low-grade tumors, while BRAF(V600E) mutations are found in high-grade malignant astrocytomas.

Area of Science:

  • Oncology
  • Genetics
  • Pediatric Cancer Research

Background:

  • Malignant astrocytomas in children are deadly tumors with limited therapeutic options due to poor understanding of their genetic basis.
  • Identifying genetic alterations is crucial for developing targeted therapies for pediatric astrocytomas.

Purpose of the Study:

  • To perform a genome-wide search for DNA copy number aberrations (CNA) in pediatric astrocytomas.
  • To identify specific genetic alterations, particularly in the BRAF gene, associated with different grades of astrocytoma.

Main Methods:

  • Genome-wide analysis of DNA copy number aberrations (CNA) in 33 pediatric astrocytoma tumors (grades 1-4).
  • Detection of gene amplifications, homozygous deletions, gene rearrangements, and specific mutations (BRAF(V600E)).
  • Analysis of KIAA1549-BRAF fusion transcripts and BRAF mutations in relation to tumor grade.

Main Results:

  • Genomic amplifications (MDM4, PDGFRA, MET, CMYC, PVT1, WNT5B, IGF1R) were found in high-grade (3-4) astrocytomas.
  • Homozygous deletions (CDKN2A, PTEN, TP53) were observed in grade 2-4 tumors.
  • KIAA1549-BRAF fusions were specific to grade 1 astrocytomas, while BRAF(V600E) mutations occurred in 7/31 of grade 2-4 tumors, often with CDKN2A deletion.

Conclusions:

  • BRAF alterations are frequent in pediatric astrocytomas, with distinct patterns observed between low-grade (grade 1) and high-grade (grades 2-4) tumors.
  • KIAA1549-BRAF fusions define a subset of pilocytic astrocytomas (grade 1).
  • BRAF(V600E) mutations, frequently co-occurring with CDKN2A deletions, characterize a subset of malignant pediatric astrocytomas, suggesting therapeutic targets.

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