Gent-48. Structural Variants in Gliomas Affect Regulatory Dna Elements and Cause Ectopic Gene Expression
Year: 2016
Type: conference-abstract
Abstract: Although somatic single nucleotide variants in coding genes have been identified through large-scale genomic sequencing efforts such as TCGA, structural variants are less well understood, in part due to less mature methods for identification of this class of structural genomic variant. Structural variations are relatively large genomic alterations (> 100bp) including deletion, duplication, insertion, inversion, translocation and complex rearrangement. Although they are less common than point mutations, they may have great impact in regulating gene expression. We used a recently developed algorithm-Lumpy, which takes advantages of both split-reads pairs and discordant reads pairs, to identify genomic rearrangements in the whole genomes of 88 TCGA glioma samples. Among them, 14 samples are IDH mutants with 1p/19q co-deletion; 24 samples are IDH mutants without 1p/19q co-deletion; 44 samples are IDH wild type and 6 glioblastoma samples with unknown IDH status. In total, we identified 12,933 high-confidence structural variants. The frequency of structural variants significantly differed between glioma subtypes: IDH wild-type gliomas harbor the most structural variants followed by IDH mutants without 1p/19q co-deletion and IDH mutants with 1p/19q co-deletion. EGFR was identified as the most frequently affected gene by duplication. MTAP and MIR31HG were frequently co-deleted with CDKN2A. Of note, 40% of the breakpoints occur in the introns while more than 50% of the breakpoints occur in the distal intergenic regions, suggesting that SVs may disrupt distal regulatory DNA elements. To investigate the mechanisms of structural variants-dysregulated gene expression, we performed H3K27ac ChIP-seq in a subset of GBM tumors and glioma sphere-forming cells to identify glioma-specific enhancers compared with normal brain tissues. We found that VEGFA gene had a de-novo gained downstream enhancer. Integrating H3K27ac profiles with genomic rearrangements identified structural variants that rearranged super-enhancer of KIAA0195 to activate CNEP1R1 expression. Our study revealed new mechanisms of oncogene activation in gliomas.
Source: Neuro-Oncology
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2587987784