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Abstract

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) remains a devastating and incurable disease. The DIPG-BATs clinical trial incorporates diagnostic biopsy with molecularly determined treatment stratification. Here we present the initial genomic analysis of the DIPG-BATs cohort. 
METHODS: Children enrolled on the DIPG-BATs clinical trial underwent upfront diagnostic biopsies prior to commencement of therapy. RNA and DNA were extracted from single core biopsies and subjected to whole-genome sequencing (WGS) and RNA-sequencing. Tumor samples were also collected at autopsy if there was parental consent. RESULTS: Fifty-three patients were enrolled on study, of whom 50 underwent biopsy. There were no biopsy-related deaths. A mean of 5ug of RNA and 10ug of DNA were extracted from single frozen cores. WGS on 41 DIPG samples (including eight autopsy samples) revealed a mean mutation rate of 0.753 mutations per Mb. We confirmed TP53, PIK3CA, H3F3A, ACVR1, PPM1D, and HIST1H3B to be recurrently mutated in DIPG. Additional mutations were found in epigenetic modifiers including ASXL1. Copy-number analysis revealed PDGFRA to meet statistical significance as a recurrent amplification peak in DIPG (q<0.25). Gene-set analysis revealed mutations in the TERT pathway, ARF pathway, AKT/PTEN pathway, TP53 pathway, cell cycle and apoptosis pathways to be statistically enriched across the cohort (q<0.10). Analysis of paired diagnosis and autopsy samples revealed evolution of tumors following treatment. Samples obtained at autopsy exhibited a significantly increased mean mutation rate compared to untreated biopsies (p<0.0001). CONCLUSIONS: Whole-genome sequencing of DIPG-BATs samples confirms driver mutations in multiple pathways implicated in cancer. Initial investigation of paired biopsy and autopsy samples allows the analysis of the genomic evolution of DIPG. These findings shed insight into both oncogenic and resistance drivers in DIPG. *equal contribution

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© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
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Abstracts > DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
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