Childhood thalamic tumors are relatively rare cancers, accounting for 5% of all pediatric brain tumors. These tumors are usually of glial origin and thalamic lesions are histologically classified as either low grade gliomas (LGG) or high grade gliomas (HGG) according to the World Health Organization (WHO) classification3. Recent molecular studies and WHO classification places thalamic tumors in the category of midline gliomas such as diffuse intrinsic pontine gliomas (DIPGs). This new categorization has been mainly based on discoveries that indicate histone 3 mutations as driver genomic aberration of these cancers. We and others have shown that mutations in genes encoding for histone 3.3 (h3f3a), histone 3.2 (hist2h3c) and histone 3.1 (hist1h3b) along with their obligate partner mutations are the major driver mutations in DIPGs. Thalamic lesions may spread to both (right and left) thalami as well as the brainstem. Bilateral thalamic gliomas (BTG) are particularly rare where the diffuse nature and bilateral involvement of the lesion indicates a poor prognosis and restricted total surgical resection. Thalamic HGGs that harbor H3.3K27M mutation are associated with worse overall survival13. Where recent studies have identified major histone partner mutations associated with DIPGs, more research is required to provide a clear landscape of genomic aberrations associated with thalamic tumors.
We hypothesize that comprehensive whole genome sequence, methylation and proteome analysis of a large cohort of thalamic tumors will map differentially regulated pathways and identify potential novel driver and obligate partner mutations associated with thalamic gliomas. We also hypothesize that primary thalamic tumor and metastatic thalamic tumors have distinctive genomic pathways that predispose the thalamic involvement. Our hypothesis are established based on the recent studies that demonstrate molecular profile of tumor often is not represented histologically. Indeed, we have shown that a histologically ‘normal’ brain section may include cells harboring histone mutations. Similarly, a recent case report of pediatric thalamic glioma demonstrated that these tumors – when positive for H3 mutation – have potential malignant transformation properties, even when standard histopathology and MRI findings fail to indicate malignancy at initial presentation16. Thus, comparing comprehensive molecular analysis of thalamic tumors (primary and metastatic) and non-thalamic midline tumors (specimen and data already in hand), will identify similarities and differences in genomic, epigenomic and proteomic expression pattern which may guide a better characterization of thalamic tumor as a separate entity.
What are the goals of this project?
The goals of this project are to generate the comprehensive molecular profile specific to primary thalamic tumors and to validate identified genomic aberrations using liquid biopsy (CSF) and whole exome sequencing (DNA from blood).
What is the impact of this project?
This project is a comprehensive study of the biology of thalamic glioma, understanding its genetic background that signifies thalamic tumors as a separate entity under CNS midline glioma, a unique comprehensive proteomic profiling that will include rare DIPG specimen and subtraction of DIPG biology in order to decipher thalamic-centric genomic aberrations
Why the CBTN request is important to this project?
The Children's Brain Tumor network provides access to a unique cohort of specimens.
The Children's Brain Tumor Network contributed to this project by providing plasma samples, tumor tissue, tumor DNA, cerebral spinal fluid and germline DNA.
Javad Nazarian, PhD, MSc
I am an investigator at the Center for Genetic Medicine in Children’s National Hospital in Washington, D.C., and an assistant professor in Integrative Systems Biology at the George Washington University. I received my PhD from the George Washington University in Genetics in 2005. My dissertation
Children’s National Hospital
Foundation and Family Partnerships
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinica
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective
Atypical teratoid/rhabdoid tumor (AT/RT)
Atypical teratoid/rhabdoid tumor (AT/RT)
Central nervous system (CNS) atypical teratoid/rhabdoid tumor (AT/RT) is a very rare, fast-growing tumor of the brain and spinal cord. It usually occurs in children aged three years and younger, although it can occur in older children and adults. About half of these tumors form in the cerebellum
Low-Grade astrocytomas are the most common cancer of the central nervous system in children. They represent a heterogeneous group of tumors that can be discovered anywhere within the brain or spinal cord. Although surgical resection may be curative, up to 20% of children still suffer from the eff
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.[
Germinomas are the most common type of CNS germ cell tumor and have a good prognosis.
Nongerminomatous Germ Cell Tumors (NGGCTs)
Primary CNS GCTs are a heterogeneous group of neoplasms that are more common in Japan and other Asian countries than in North America and Europe. In North America, they account for approximately 4% of all primary brain tumors, with a peak incidence from age 10 years to age 19 years and a male pre