DIPG-50. A NOVEL ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODEL OF RADIATION-INDUCED GLIOMA. (4th December 2020)

• Record Type: Journal Article
• Authors: Whitehouse, Jacqueline; Howlett, Meegan; Stanley, Jason; Hii, Hilary; Valvi, Santosh; White, Christine; Mayoh, Chelsea; Wong, Marie; Strowger, Brooke; Dyke, Jason; Cowley, Mark; Gottardo, Nicholas; Endersby, Raelene
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 3
• Page Start: iii296
• Page End: iii296
• Publication Date: 2020-12-04
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa222.095
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Diffuse midline glioma (DMG) can arise as a primary tumour but also as a consequence of radiation therapy (RT) in survivors of other paediatric brain tumours. Radiation-associated gliomas are molecularly distinct from primary gliomas and have poorer overall survival. We report a case of radiation-associated DMG following treatment for medulloblastoma, and the development of a matched patient-derived xenograft (PDX) model. A four-year-old boy diagnosed with medulloblastoma was treated with surgical resection, RT and chemotherapy (COG:CCG-99701-Arm B). Eleven years post-diagnosis, the patient relapsed with radiation-associated DMG, participated in a Phase I clinical trial (COG:ACNS0927), and passed away eight months later. Tumour tissue collected at autopsy was intracranially implanted into immunodeficient mice and serially transplanted in vivo . Immunohistochemistry demonstrated both the primary DMG and PDXs expressed PDGFR-alpha and PTEN, were H3K27me3-positive, and had undetectable levels of p53. Sequencing revealed an activating mutation in PI3-kinase (H1047L) and variants of unknown significance in GRK4, FLG, BAZ2A, and CRTC3 . DNA methylation array of the PDX demonstrated 1p loss, which is not typically associated with primary DMG, and broad deletion within 9p including CDKN2A/B, MTAP and multiple interferon genes. The methylation profile did not significantly classify with other tumours in the Molecular Neuropathology database (molecularneuropathology.org/mnp). We describe the first reported PDX model of radiation-associated DMG following medulloblastoma, which recapitulates the patient disease and is molecularly distinct from primary DMG. Interrogation of this model through RNA and whole genome sequencing presents a valuable opportunity to better understand and identify novel therapeutic vulnerabilities against this currently incurable disease.