Abstract
Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children’s Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.
Highlights
Pediatric brain tumors are a leading cause of non-accidental death in children
We found that the latency of tumor growth from the time of implant to tumor harvest was remarkably unchanged from one passage to the for all Patient-derived orthotopic xenografts (PDOX) regardless of aggressivity or molecular features
We report 37 new PDOX models representing the immortalization of several pediatric brain tumor entities and their associated subgroups, including MB, atypical teratoid rhabdoid tumors (AT/RT), EPN, and embryonal tumor with multi-layer rosettes (ETMR), many of which have no representation amongst published genetically engineered mouse (GEM) or PDOX models
Summary
3200 children are diagnosed with brain tumors in the United States each year; mortality amongst affected children is disproportionately concentrated within five malignant central nervous system (CNS) tumor entities [31]. These include high-grade gliomas (HGG), medulloblastomas (MB), ependymomas (EPN), atypical teratoid rhabdoid tumors (AT/RT), and. PNET was a term previously used to broadly capture all embryonal tumors. This designation has recently been retired in favor of more specific terminology and from hereon, we used the updated entity designations such as embryonal tumor with multi-layer rosettes (ETMR) or CNS embryonal tumor with rhabdoid features, as appropriate [23, 42]. Even survival comes at a price, and significant treatment-associated sequelae, including moderate-to-severe neurocognitive, neuroendocrine, and psychosocial deficits, affect survivors and compromise their quality of life
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