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dc.contributor.authorClarke, M
dc.date.accessioned2021-09-28T13:49:57Z
dc.date.available2021-10-30T00:00:00Z
dc.date.issued2021-04-30
dc.identifier.citation2021
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4832
dc.description.abstractInfant high grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumours. I have collected 241 cases under 4 years of age, and carried out histological review, methylation profiling, custom DNA fusion panel and whole genome/exome sequencing. After excluding tumours representing other established biological entities or subgroups, I identified 130 cases to be part of an intrinsic spectrum of disease specific to infant population (~80% aged <1 year), the majority of which represented a relatively new tumour currently called 'infant hemispheric glioma' (IHG). These tumours were found to be enriched for the presence of targetable MAP-kinase alterations, with nearly two-thirds of remaining cases harbouring gene fusions targeting ALK, NTRK1/2/3, ROS1 and MET as their sole driving alterations. For the most part, these could be identified by small intragenic DNA copy number variants detectable in the methylation array data, and a review of publicly available methylation datasets (n=5660, half paediatric) showed that gene fusions were also present in gliomas outside of the infant population but at lower frequency. Novel NTRK2 fusions were introduced into brain progenitor cells to explore their functional consequences, and patient-derived cell cultures of infant glioma harbouring various NTRK fusions were found to show differential efficacy for NTRK inhibitors. I further describe multiple cases of fusion-positive patients treated clinically with ALK or NTRK inhibitors who have responded to the drugs, even after progressing on standard chemotherapies. I have additionally profiled a series of cases for which longitudinal samples are available, exploring copy number and mutational differences post-therapy. Overall, the intrinsic group of infant glioma cases were found to have a significantly improved outcome compared to cases classified as high grade gliomas, with a median overall survival similar to those considered as low grade gliomas. These data strongly supports that infant gliomas require a change in both their diagnostic practice and management.
dc.language.isoeng
dc.subjectTheses, Doctoral
dc.subjectGlioma - Molecular Pathology
dc.titleThe molecular pathology of infant gliomas
dc.typeThesis
rioxxterms.versionAO
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-04-30en_US
rioxxterms.typeThesis
pubs.notes6 months
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.embargo.terms6 months
pubs.embargo.date2021-10-30T00:00:00Z
icr.researchteamGlioma Teamen_US
dc.contributor.icrauthorClarke, Matthewen


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