A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma

Abstract

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.

Defining the molecular features of radiation-induced glioma: A systematic review and meta-analysis

“… 57–59 A small cytogenetic study of 3 RIGs reported extremely complex karyotypes 18 ; however, few studies have extensively examined broad chromosomal gains or losses in cranial RIGs. Paugh et al 33 performed the largest analysis to date examining 10 RIG samples, to which we have added seven more cases here 34 , 40 , 43 , 49 ( Figure 3 and Supplementary Tables 2 and 3 ). Overall, the most frequent copy number changes observed in RIGs were loss of 13q (observed in 59% of samples reported), gain of 1q (53%), and loss of 1p (47%).…”

“…Blue indicates loss and red indicates gain of chromosomal arms, with percentages of cases reporting gain or loss for each arm shown. 33 , 34 , 40 , 43 , 49 …”

“…Some tumors harbored multiple genetic alterations; data shown represent all reported genetic alterations for that location, and do not imply mutual exclusivity of genetic alterations within tumors. 19 , 22 , 25 , 28 , 40 , 46 (B) Scatter plot of latency intervals for RIGs arising in the three defined brain regions. 18 , 19 , 22 , 23 , 25–32 , 34–38 , 40–42 , 45–48 , 50 Bars show mean ± SD.…”

Assessment of Cannabidiol and Δ9-Tetrahydrocannabiol in Mouse Models of Medulloblastoma and Ependymoma

“…While our understanding of the molecular pathogenesis of these diseases has improved dramatically in the last three decades, this knowledge has not translated to increased patient survival. Amongst survivors, current treatments can cause debilitating side effects, including untreatable secondary malignancies [ 13 ], cognitive dysfunction, cardiotoxicity, myelosuppression, renal toxicity, and endocrine problems [ 14 ]. Therefore, improved clinical outcomes are dependent on the identification of efficacious therapies that not only increase survival but reduce treatment-related side effects.…”

Rare Childhood Malignancy

“…This small collection of six original research papers and two review articles in the Special Issue “Rare Childhood Malignancy” highlights the diversity and importance of empirical research into childhood malignancy, a theme that underpins the significant advances that have been made in treating the diseases that constitute cancers in children. These articles cover significant themes in childhood cancer research and include biological studies on the role of MYCN in poor prognosis Wilms’ tumor [ 1 ] and the mTOR complexes in rhabdomyosarcoma [ 2 ]; studies exploring biologically based treatments in ependymoma [ 3 ] and osteosarcoma [ 4 ]; a comprehensive description of a novel orthotopic model for radiation-induced glioma which will be invaluable for preclinical testing [ 5 ]; and two comprehensive review articles on leukemias. One review describes recently identified rearrangements of DUX4 with IGH in childhood B-cell acute lymphoblastic leukemia (ALL) and the diagnostic challenges associated with identifying the rearrangement [ 6 ], and the second proposes that infant acute myeloid leukemia (AML) is a biologically and clinically distinct entity from AML in older children [ 7 ].…”