dc.contributor.author | Koschmann, C | |
dc.contributor.author | Zamler, D | |
dc.contributor.author | MacKay, A | |
dc.contributor.author | Robinson, D | |
dc.contributor.author | Wu, Y-M | |
dc.contributor.author | Doherty, R | |
dc.contributor.author | Marini, B | |
dc.contributor.author | Tran, D | |
dc.contributor.author | Garton, H | |
dc.contributor.author | Muraszko, K | |
dc.contributor.author | Robertson, P | |
dc.contributor.author | Leonard, M | |
dc.contributor.author | Zhao, L | |
dc.contributor.author | Bixby, D | |
dc.contributor.author | Peterson, L | |
dc.contributor.author | Camelo-Piragua, S | |
dc.contributor.author | Jones, C | |
dc.contributor.author | Mody, R | |
dc.contributor.author | Lowenstein, PR | |
dc.contributor.author | Castro, MG | |
dc.date.accessioned | 2016-09-28T09:35:43Z | |
dc.date.issued | 2016-10-04 | |
dc.identifier.citation | Oncotarget, 2016, 7 (40), pp. 65696 - 65706 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/123 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.11602 | |
dc.description.abstract | Pediatric high-grade glioma (HGG, WHO Grade III and IV) is a devastating brain tumor with a median survival of less than two years. PDGFRA is frequently mutated/ amplified in pediatric HGG, but the significance of this finding has not been fully characterized. We hypothesize that alterations of PDGFRA will promote distinct prognostic and treatment implications in pediatric HGG. In order to characterize the impact of PDGFR pathway alterations, we integrated genomic data from pediatric HGG patients (n=290) from multiple pediatric datasets and sequencing platforms. Integration of multiple human datasets showed that PDGFRA mutation, but not amplification, was associated with older age in pediatric HGG (P= <0.0001). In multivariate analysis, PDGFRA mutation was correlated with worse prognosis (P = 0.026), while PDGFRA amplification was not (P = 0.11). By Kaplan-Meier analysis, non-brainstem HGG with PDGFRA amplification carried a worse prognosis than non-brainstem HGG without PDGFRA amplification (P = 0.021). There were no pediatric patients with PDGFRA-amplified HGG that survived longer than two years. Additionally, we performed paired molecular profiling (germline / tumor / primary cell culture) and targeting of an infant thalamic HGG with amplification and outlier increased expression of PDGFRA. Dasatinib inhibited proliferation most effectively. In summary, integration of the largest genomic dataset of pediatric HGG to date, allowed us to highlight that PDGFRA mutation is found in older pediatric patients and that PDGFRA amplification is prognostic in non-brainstem HGG. Future precision-medicine based clinical trials for pediatric patients with PDGFRA-altered HGG should consider the optimized delivery of dasatinib. | |
dc.format | Print | |
dc.format.extent | 65696 - 65706 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Tumor Cells, Cultured | |
dc.subject | Humans | |
dc.subject | Glioma | |
dc.subject | Brain Neoplasms | |
dc.subject | Receptor, Platelet-Derived Growth Factor alpha | |
dc.subject | Antineoplastic Agents | |
dc.subject | Survival Rate | |
dc.subject | Follow-Up Studies | |
dc.subject | Age Factors | |
dc.subject | Apoptosis | |
dc.subject | Cell Proliferation | |
dc.subject | Gene Amplification | |
dc.subject | Mutation | |
dc.subject | Adolescent | |
dc.subject | Adult | |
dc.subject | Child | |
dc.subject | Child, Preschool | |
dc.subject | Infant | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Young Adult | |
dc.subject | Neoplasm Grading | |
dc.subject | Biomarkers, Tumor | |
dc.title | Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-08-13 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.11602 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-10 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 40 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Glioma Team | |
dc.contributor.icrauthor | Mackay, Alan | |
dc.contributor.icrauthor | Jones, Chris | |