EPCO-17. UNMASKING CLONAL EVOLUTION OF DIFFUSE INTRINSIC GLIOMA USING MULTI-MODAL GENOMIC DATA. (14th November 2022)

• Record Type: Journal Article
• Authors: Patel, Palak; Ryall, Scott; Turinsky, Andrei; Siddaway, Robert; Pajovic, Sanja; Buczkowicz, Pawel; Brudno, Michael; Ramani, Arun; Hawkins, Cynthia
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 7
• Page Start: vii119
• Page End: vii119
• Publication Date: 2022-11-14
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac209.452
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Diffuse intrinsic pontine glioma (DIPG) is an infiltrative incurable tumor affecting children. DIPG tumors often harbor a recurrent H3K27M mutation which leads to a global loss of H3K27me2/3 and overall DNA hypomethylation, suggesting an important role of the epigenome, and consequent transcriptome in DIPG pathogenesis. To thoroughly characterize the clonal evolution of DIPG, we collected 33 samples from 7 DIPG patients using a multi-region sampling strategy and generated whole-exome and transcriptome sequencing, and DNA methylation profiling data. Using our novel bioinformatics approach, 28 distinct tumor sub-clones were identified and characterized in our cohort of DIPG patients whilst simultaneously interrogating the tumor's ability to migrate and disseminate. When present, initiating tumor clone (Clone 1) exclusively contained H3K27M with significant DNA methylation changes whereas the divergent clones that arise later in DIPG evolutionary trees were typically driven by the copy number aberrations. Further characterization of DIPG sub-clones identified unique gene expression profiles ( i.e. cell migration and angiogenesis programs) that support and enable DIPG dissemination. In this study, we uncovered how DIPG evolves at the genetic, epigenetic, and transcriptional levels in parallel and in doing so, reveal novel evolutionary phenotypes at the sub-clonal level related to the tumor's behavior. We are further validating these results in single-cell RNA sequencing experiments and gaining further insights into the underlying molecular mechanisms responsible for invasive and aggressive DIPG phenotypes.