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Br J Cancer ; 101(4): 722-33, 2009 Aug 18.
Article in English | MEDLINE | ID: mdl-19603027

ABSTRACT

BACKGROUND: Juvenile pilocytic astrocytomas (JPA), a subgroup of low-grade astrocytomas (LGA), are common, heterogeneous and poorly understood subset of brain tumours in children. Chromosomal 7q34 duplication leading to fusion genes formed between KIAA1549 and BRAF and subsequent constitutive activation of BRAF was recently identified in a proportion of LGA, and may be involved in their pathogenesis. Our aim was to investigate additional chromosomal unbalances in LGA and whether incidence of 7q34 duplication is associated with tumour type or location. METHODS AND RESULTS: Using Illumina-Human-Hap300-Duo and 610-Quad high-resolution-SNP-based arrays and quantitative PCR on genes of interest, we investigated 84 paediatric LGA. We demonstrate that 7q34 duplication is specific to sporadic JPA (35 of 53 - 66%) and does not occur in other LGA subtypes (0 of 27) or NF1-associated-JPA (0 of 4). We also establish that it is site specific as it occurs in the majority of cerebellar JPA (24 of 30 - 80%) followed by brainstem, hypothalamic/optic pathway JPA (10 of 16 - 62.5%) and is rare in hemispheric JPA (1 of 7 - 14%). The MAP-kinase pathway, assessed through ERK phosphorylation, was active in all tumours regardless of 7q34 duplication. Gain of function studies performed on hTERT-immortalised astrocytes show that overexpression of wild-type BRAF does not increase cell proliferation or baseline MAPK signalling even if it sensitises cells to EGFR stimulation. CONCLUSIONS AND INTERPRETATION: Our results suggest that variants of JPA might arise from a unique site-restricted progenitor cell where 7q34 duplication, a hallmark of this tumour-type in association to MAPK-kinase pathway activation, potentially plays a site-specific role in their pathogenesis. Importantly, gain of function abnormalities in components of MAP-Kinase signalling are potentially present in all JPA making this tumour amenable to therapeutic targeting of this pathway.


Subject(s)
Astrocytoma/genetics , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Chromosomes, Human, Pair 7/genetics , Adolescent , Astrocytoma/metabolism , Astrocytoma/pathology , Blotting, Western , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Carrier Proteins/genetics , Child , Child, Preschool , Female , Fluorescent Antibody Technique , Gene Dosage , Gene Duplication , Humans , Immunohistochemistry , Male , Mitogen-Activated Protein Kinases/metabolism , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins B-raf/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/physiology
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