Pediatric High Grade Glioma Resources From the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pediatric Brain Tumor Atlas (PBTA)

Abstract

Background: Pediatric high grade glioma (pHGG) remains a fatal disease. Increased access to richly annotated biospecimens and patient derived tumor models will accelerate pHGG research and support translation of research discoveries. This work describes the pediatric high grade glioma set of the Children's Brain Tumor Tissue Consortium (CBTTC) from the first release (October 2018) of the Pediatric Brain Tumor Atlas (PBTA).Methods: pHGG tumors with associated clinical data and imaging were prospectively collected through the CBTTC and analyzed as the Pediatric Brain Tumor Atlas (PBTA) with processed genomic data deposited into PedcBioPortal for broad access and visualization. Matched tumor was cultured to create high grade glioma cell lines analyzed by targeted and WGS and RNA-seq. A tissue microarray (TMA) of primary pHGG tumors was also created. Results:The pHGG set included 87 collection events (73 patients, 60% at diagnosis, median age of 9 yrs, 55% female, 46% hemispheric). Analysis of somatic mutations and copy number alterations of known glioma genes were of expected distribution (36% H3.3, 47% TP53, 24% ATRX and 7% BRAF V600E variants). A pHGG TMA (n=77), includes 36 (53%) patient tumors with matched sequencing. At least one established glioma cell line was generated from 23 patients (32%). Unique reagents include those derived from a H3.3 G34R glioma and from tumors with mismatch repair deficiency. Conclusion:The CBTTC and PBTA have created an openly available integrated resource of over 2,000 tumors, including a rich set of pHGG primary tumors, corresponding cell lines and archival fixed tissue to advance translational research for pHGG.

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

“…Hedgehog, TNFα , and p53 signaling were enriched in these models (Figure 5B). Interestingly, three astrocytic tumors harbored SMARCB1 hemizygous deletions, which have not been reported but are present in multiple pediatric high-grade glioma cohorts (Mackay et al, 2017: 6.7%, n = 834; Ijaz et al, 2019: 7.5%, n = 93) and may warrant further investigation. One astrocytic model, IC-1621GBM, was generated from a patient with DNA mismatch repair deficiency syndrome and showed 124 somatic mutations per medulloblastoma (MB) (Table S3).…”

A pediatric brain tumor atlas of genes deregulated by somatic genomic rearrangement

“…The Children’s Brain Tumor Tissue Consortium (CBTTC) ( https://cbttc.org ) is an international, collaborative, and multi-institutional research program dedicated to studying childhood brain tumors 8 . CBTTC efforts include providing open access genomics data on pediatric brain tumors to the research community to more fully elucidate these tumors’ molecular landscape.…”

annoFuse: an R Package to annotate, prioritize, and interactively explore putative oncogenic RNA fusions

“…As proof of concept, we utilized RNA expression generated by STAR-RSEM [ 42 ] and fusion calls generated by Arriba v1.1.0 [ 15 ] and/or STAR-Fusion 1.5.0 [ 14 ] which were released as part of the Pediatric Brain Tumor Atlas [ 43 ]. Briefly, RNA from fresh-frozen tissue was extracted and libraries were prepped and sequenced at 2 × 100 or 2 × 150 bp to an average of 200 M+ total reads, and at least 60% of reads were required to map to the human genome for fusion analysis to proceed.…”