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Abstract
Glioblastoma Multiforme (GBM) is the most frequent and lethal primary brain cancer. Due to its therapeutic resistance and aggressiveness, its clinical management is challenging. Platelet-derived Growth Factor (PDGF) genes have been enrolled as drivers of this tumour progression as well as potential therapeutic targets. As detailed understanding of the expression pattern of PDGF system in the context of GBM intra- and intertumoral heterogeneity is lacking in the literature, this study aims at characterising PDGF expression in different histologically-defined GBM regions as well as investigating correlation of these genes expression with parameters related to poor prognosis. Z-score normalised expression values of PDGF subunits from multiple slices of 36 GBMs, alongside with clinical and genomic data on those GBMs patients, were compiled from Ivy Glioblastoma Atlas Project – Allen Institute for Brain Science data sets. PDGF subunits show differential expression over distinct regions of GBM and PDGF family is heterogeneously expressed among different brain lobes affected by GBM. Further, PDGF family expression correlates with bad prognosis factors: age at GBM diagnosis, Phosphatase and Tensin Homolog deletion and Isocitrate Dehydrogenase 1 mutation. These findings may aid on clinical management of GBM and development of targeted curative therapies against this devastating tumour.
Highlights
For their prominent influence in Glioblastoma Multiforme (GBM) development, and in keeping with the perspective of molecular-based curative treatments of this tumour, Platelet-derived Growth Factor (PDGF) genes have been suggested as GBM therapeutic targets and clinical trials have been performed with inhibitors of tyrosine kinase receptors such as Imatinib, which showed only limited beneficial effects
Rates of Phosphatase and Tensin Homolog (PTEN) loss and Isocitrate Dehydrogenase 1 (IDH1) mutation at R132 were consistent with frequencies reported in the literature: PTEN deletion is considered to be a driver alteration very commonly associated with GBM13, whereas IDH1 mutation is described as being much more prevalent in secondary GBM, rather than in primary tumours[14], which are being studied here
This study presents a broad perspective on the inter- and intratumoral heterogeneity of the PDGF family expression in GBMs, along with the potential prognostic significance of these genes expression, from analysis of the comprehensive database of the Ivy Glioblastoma Atlas Project – Allen Institute for Brain Science
Summary
For their prominent influence in GBM development, and in keeping with the perspective of molecular-based curative treatments of this tumour, PDGF genes have been suggested as GBM therapeutic targets and clinical trials have been performed with inhibitors of tyrosine kinase receptors such as Imatinib, which showed only limited beneficial effects. Heterogeneity is a hallmark of GBM8 and is thought not to be appreciated by current diagnostic and assessment method of single biopsy and whole tissue analysis of a GBM9. This is likely to give a poor perspective of how is the tumour molecular panel configured and how its already well-described biomarkers www.nature.com/scientificreports/. Are distributed in each single tumour block, which has a direct negative impact on the development of successful targeted therapies
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