ID #1112 Identification of novel PDGFRA activating intragenic deletions in paediatric high-grade glioma

Abstract

Personalised medicine initiatives like the Zero Childhood Cancer Program (ZERO) uses comprehensive molecular profiling to match cancer therapies to the individual tumour biology of each patient. Unbiased sequencing approaches, including whole-genome sequencing (WGS) and transcriptome sequencing (RNA-seq), enable detection of structural variants and can reveal novel oncogenic drivers and actionable alterations that guide targeted treatment strategies. This is particularly important for paediatric high-grade glioma (pHGG), an aggressive malignancy with poor prognosis and limited effective therapeutic options.

Platelet-derived growth factor receptor alpha (PDGFRA), a receptor tyrosine kinase (RTK) implicated in gliomagenesis, represents an attractive therapeutic target given the availability of multi-kinase TKIs and PDGFRA-directed inhibitors. PDGFRA is frequently altered in high-grade glioma, commonly through amplification and rearrangements. Using WGS/RNA-seq, we identified two PDGFRA intragenic deletions in pHGG: a novel PDGFRAΔ2,9 deletion and the previously described (in adult HGG) PDGFRAΔ8,9 deletion. Consistent with adult HGG, the paediatric PDGFRAΔ8,9 case also exhibited PDGFRA amplification. Structurally, PDGFRAΔ2,9 deletes the extracellular domain, retaining only a small portion of the Ig-5 domain, whereas PDGFRAΔ8,9 results in an 81-amino-acid deletion spanning part of the Ig-4 and Ig-5 domains.

To evaluate oncogenic potential, we overexpressed PDGFRAΔ2,9, PDGFRAΔ8,9, and wild-type PDGFRA in the interleukin-3 (IL-3)-dependent Ba/F3 cell model. Both PDGFRAΔ2,9 and PDGFRAΔ8,9 conferred IL-3-independent survival and proliferation, consistent with constitutive activation of PDGFRA signalling. Importantly, cells transformed by either variant were sensitive to dasatinib treatment. Localisation studies further demonstrated that PDGFRAΔ2,9 does not localise to the cell surface, whereas PDGFRAΔ8,9 retains surface localisation.

Together, these findings identify novel PDGFRA deletion variants in pHGG and support PDGFRA inhibition as a potential therapeutic strategy for this molecular subgroup.