{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:49:54Z","timestamp":1773816594184,"version":"3.50.1"},"reference-count":87,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T00:00:00Z","timestamp":1602460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Pirate Ship Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100016057","name":"Robert Connor Dawes Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100016057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Carrie's Beanies for Brain Cancer","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100001111","name":"Cancer Australia","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001111","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004752","name":"State Government of Victoria","doi-asserted-by":"publisher","award":["Operational Infrastructure Support Program"],"award-info":[{"award-number":["Operational Infrastructure Support Program"]}],"id":[{"id":"10.13039\/501100004752","id-type":"DOI","asserted-by":"publisher"}]},{"name":"My Room","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100008810","name":"NSW Ministry of Health","doi-asserted-by":"publisher","award":["Luminesce Alliance"],"award-info":[{"award-number":["Luminesce Alliance"]}],"id":[{"id":"10.13039\/501100008810","id-type":"DOI","asserted-by":"publisher"}]},{"name":"John Lillie Cancer Research Fellowship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100001170","name":"Cancer Council Western Australia","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001170","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stan Perron Charitable Foundation","award":["Stan Perron Chair of Paediatric Haematology and Oncology"],"award-info":[{"award-number":["Stan Perron Chair of Paediatric Haematology and Oncology"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K\/AKT and Ras\/Raf\/MEK\/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A\/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phosphorylated S6, 4EBP1 and ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.<\/jats:p>","DOI":"10.3390\/cancers12102937","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T21:42:21Z","timestamp":1602798141000},"page":"2937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Jacqueline P.","family":"Whitehouse","sequence":"first","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"},{"name":"Centre for Child Health Research, University of Western Australia, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4332-6572","authenticated-orcid":false,"given":"Meegan","family":"Howlett","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"},{"name":"Centre for Child Health Research, University of Western Australia, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary","family":"Hii","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6398-3046","authenticated-orcid":false,"given":"Chelsea","family":"Mayoh","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington 2033, Australia"},{"name":"School of Women\u2019s and Children\u2019s Health, UNSW Sydney, Kensington 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0066-6606","authenticated-orcid":false,"given":"Marie","family":"Wong","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington 2033, Australia"},{"name":"School of Women\u2019s and Children\u2019s Health, UNSW Sydney, Kensington 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulette","family":"Barahona","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela","family":"Ajuyah","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5920-0029","authenticated-orcid":false,"given":"Christine L.","family":"White","sequence":"additional","affiliation":[{"name":"Genetics and Molecular Pathology Laboratory, Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia"},{"name":"Department of Molecular and Translational Science, Monash University, Melbourne 3168, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molly K.","family":"Buntine","sequence":"additional","affiliation":[{"name":"Genetics and Molecular Pathology Laboratory, Hudson Institute of Medical Research, Clayton 3168, Victoria, Australia"},{"name":"Department of Molecular and Translational Science, Monash University, Melbourne 3168, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8152-6252","authenticated-orcid":false,"given":"Jason M.","family":"Dyke","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, PathWest Laboratory Medicine, Royal Perth Hospital, Perth 6000, Australia"},{"name":"Pathology and Laboratory Medicine, University of Western Australia, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Perth Children\u2019s Hospital, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santosh","family":"Valvi","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"},{"name":"Department of Paediatric and Adolescent Oncology\/Haematology, Perth Children\u2019s Hospital, Nedlands 6009, Australia"},{"name":"Division of Paediatrics, University of Western Australia Medical School, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-4455","authenticated-orcid":false,"given":"Jason","family":"Stanley","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"},{"name":"Centre for Child Health Research, University of Western Australia, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-0932","authenticated-orcid":false,"given":"Clara","family":"Andradas","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"},{"name":"Centre for Child Health Research, University of Western Australia, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8061-4170","authenticated-orcid":false,"given":"Brooke","family":"Carline","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mani","family":"Kuchibhotla","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul G.","family":"Ekert","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington 2033, Australia"},{"name":"School of Women\u2019s and Children\u2019s Health, UNSW Sydney, Kensington 2033, Australia"},{"name":"Murdoch Children\u2019s Research Institute, Royal Children\u2019s Hospital, Parkville 3052, Victoria, Australia"},{"name":"Peter MacCallum Cancer Centre, Melbourne 3000, Victoria, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9519-5714","authenticated-orcid":false,"given":"Mark J.","family":"Cowley","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington 2033, Australia"},{"name":"School of Women\u2019s and Children\u2019s Health, UNSW Sydney, Kensington 2033, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas G.","family":"Gottardo","sequence":"additional","affiliation":[{"name":"Brain Tumour Research Program, Telethon Kids Institute, Nedlands 6009, Australia"},{"name":"Centre for Child Health Research, University of Western Australia, Nedlands 6009, Australia"},{"name":"Department of Paediatric and Adolescent Oncology\/Haematology, Perth Children\u2019s Hospital, Nedlands 6009, 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