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PAIS experiment

ABSTRACT: Intimal sarcoma (IS) is a rare, malignant and aggressive tumor that shows a relentless course with a concomitant low survival rate, for which no effective treatment is available. In this study, 21 cases of large arterial blood vessel IS were analyzed by immunohistochemistry and fluorescent in situ hydridisation (FISH), and selectively by karyotyping, array-CGH, sequencing, phospho-kinase antibody arrays and Western immunoblotting, in search for the novel diagnostic markers and potential molecular targets. Ex vivo immunoassays were applied to test the sensitivity of IS primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib.We demonstrated that amplification of the platelet-derived growth factor receptor alpha (PDGFRA) is a common finding in IS, and might be considered as a cytogenetic hallmark of this entity. This amplification is consistently associated with PDGFRA activation. Furthermore, the tumors reveal persistent activation of the epidermal growth factor receptor (EGFR), concurrent to PDGFRA activation. Activated PDGFRA and EGFR frequently co-exist with amplification and overexpression of MDM2. Ex vivo immunoassays on primary cells showed the potency of dasatinib to inhibit PDGFRA and downstream effectors in IS. Our findings provide a rationale for investigating therapies that target PDGFRA, EGFR or MDM2 in IS. Given the molecular heterogeneity of this tumor type and the potential crosstalk between PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve therapeutic outcome for patients with this disease. Key words: intimal sarcoma, PDGFRA, EGFR, MDM2, targeted therapy, amplification

ORGANISM(S): Homo sapiens

PROVIDER: GSE21530 | GEO | 2010/05/20

SECONDARY ACCESSION(S): PRJNA125933

REPOSITORIES: GEO

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Project description:The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10-30%. Approximately half of pediatric HGGs are diffuse intrinsic pontine glioma (DIPG), a brainstem tumor that arises almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs. To determine whether the PDGFRA is also targeted by more subtle mutations not detected by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 non-brainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFR in childhood HGG. To better understand the consequence of PDGFRα mutation in pediatric gliomagenesis, retroviral constructs expressing wild-type PDGFRα or six selected PDGFRα mutants that affect different regions of the receptor were generated for functional studies. p53-null primary mouse astrocyte (PMA) cultures were chosen as a relevant cellular background to assess PDGFRα function.

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PAIS experiment

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