Brain tumors are the most common pediatric solid tumor, affecting 1-5 per 100,000 children. While advancements in cancer therapies have led to an improved survival rate in certain brain cancers, many brain tumor types are poorly understood and lack effective treatment options. Certain subtypes of ependymoma and diffuse intrinsic pontine glioma (DIPG) brain tumors are associated with poor clinical outcomes. Ependymoma arises from ependymal cells lining the ventricles and is associated with a silent or balanced genomic profile. DIPG is an inoperable and diffuse tumor that arises in the pons and is associated with histone H3 K27M mutation, often referred to as an onco-histone. Interestingly, reduced global H3K27me3 has been identified in both posterior fossa Group A (PFA) ependymoma and DIPG. Although great effort has been taken to understand the molecular basis of PFA and DIPG, both tumor types lack identification of molecular targets responsive to chemotherapeutics. For both ependymoma and DIPG, immunotherapy is a newer option that is currently undergoing assessment. However, immunoprofiling of both diseases has been minimal and current data suggests that the tumor infiltrating leukocytes may be deficient in specific cell populations.
The goal of this study is to better understand brain cancer development and resistance to treatment through the study and combinatorial analysis of tumor genomics/transcriptomics/epigenomics and immune signatures. In ependymoma, higher numbers of CD4 T cells are predictive of good clinical outcomes and a non-recurrent phenotype. We would predict that immunogenicity differs between recurrent and non-recurrent tumors and likely between subgroups of ependymoma, as group B ependymoma with RELA-fusion is typically associated with chromothripsis which may result in the development of neoantigens. We hypothesize that similar transcriptomic signatures will be shared between posterior fossa Group A ependymoma and DIPG associated with H3 K27M mutation that are distinguishable from Group B ependymoma and H3 K27M wild type. We also hypothesize that we will identify key epigenomic signatures within the DIPG cohort that will lead to additional subtyping as well as the potential identification of novel targeted treatment options. Through this comprehensive approach, we will be able to use precision medicine to inform therapeutic decisions and gain insight into global disease mechanisms.
What are the goals of this project?
This study will perform a retrospective analysis of ependymoma data to evaluate genomic and transcriptomic profiles and immune signatures, elucidate the transcriptomic and dynamic epigenomic landscape of DIPG tumors and perform a comparative analysis of ependymoma and DIPG.
What is the impact of this project?
Although both ependymoma and DIPG have undergone evaluation at the transcriptomic and epigenomic levels, both suffer from a lack viable treatment options. By taking a comprehensive approach, including the immune response, and comparison of these two disease types, we aim to identify novel therapeutic molecular targets. Furthermore, this study aims to identify the effects of aberrant epigenetic modifications and to identify “tumor” and “normal” chromatin profiles, which could be used for future clinical prognostic and diagnostic tools through detection of fundamental epigenomic changes and signatures. Additionally, the downstream effects of anomalous epigenetic modifications have not yet been determined but could aid in a better understanding of disease etiology. Ultimately, this work will offer insight into disease mechanism and could lead to identification of novel biomarkers and therapeutic targets.
Why the CBTN request is important to this project?
Our group has extensive experience in next-generation sequencing and analysis of tumor genomes, but we are in the initial stages of starting a neuro-oncology tumor bank. We are prospectively recruiting new patients but, as both tumor types are rare, it will require a substantial amount of time to obtain the number of samples for the statistical power required for a group-wise comparison. Additionally, much of the work on ependymoma has been performed by one group and while samples were recruited from multiple institutions, none of those institutions are represented in CBTN. This will allow us to study a unique cohort relative to the currently reported literature.
The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas.
Richard Graham, St. Jude Children's Hospital
Blake Sells, Ohio State University Wexner Medical Center
Jessica Fleming, Ohio State University Wexner Medical Center
Richard K. Wilson, PhD
Dr. Wilson is an internationally recognized expert in molecular genetics and large-scale genomics, and his laboratories have been among the world’s leaders in genome analysis. His teams have sequenced and analyzed billions of bases of DNA from the genomes of bacteria, yeast, plants, invertebrates
Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord. Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial or infratentorial. In children, most ependymomas are infratentorial tumo
Brainstem glioma- Diffuse intrinsic pontine glioma
A presumptive diagnosis of DIPG based on classic imaging features, in the absence of a histologic diagnosis, has been routinely employed. Increasingly however, histologic confirmation is obtained for both entry into research studies and molecular characterization of the tumor.[