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.
