Comprehensive Molecular Analysis of Pediatric Thalamic tumors

Email Principal Investigator
Atypical teratoid/rhabdoid tumor (AT/RT)

Supratentorial or Spinal Cord PNET

choroid plexus carcinoma

About this


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.

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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.

Specimen Data

The Children's Brain Tumor Network contributed to this project by providing plasma samples, tumor tissue, tumor DNA, cerebral spinal fluid and germline DNA.