Abstract
Glioma is the most common malignant primary brain tumor and is associated with poor prognosis. Genetic factors contributing to glioma risk have recently been investigated through genome-wide association studies (GWAS), implicating seven independent glioma risk loci in six chromosomal regions. Here, we performed an in-depth functional analysis of the risk locus proximal to the PHLDB1 gene on 11q23.3. We retrieved all SNPs in linkage disequilibrium (r(2) ≥ 0.2) with the glioma-associated SNP (rs498872) and performed a comprehensive bioinformatics and experimental functional analysis for the region. After testing candidate SNPs for allele-specific activity in a luciferase-based enhancer scanning assay, we established a subset of 10 functional SNPs in the promoters of PHLDB1 and DDX6, and in a putative enhancer element. Chromatin conformation capture (3C) identified a physical interaction between the enhancer element containing a functional SNP (rs73001406) and the promoter of the DDX6 gene. Knockdown experiments in cell culture and 3D assays to evaluate the role of PHLDB1 and DDX6 suggest that both genes may contribute to the phenotype. These studies reveal the functional landscape of the 11q23.3 glioma susceptibility locus and identify a network of functional SNPs in regulatory elements and two target genes as a possible mechanism driving glioma risk association.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Brain Neoplasms / diagnosis
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Brain Neoplasms / genetics*
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Chromatin / chemistry
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Chromatin / metabolism
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Chromosomes, Human, Pair 11
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Computational Biology
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DEAD-box RNA Helicases / antagonists & inhibitors
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DEAD-box RNA Helicases / genetics*
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DEAD-box RNA Helicases / metabolism
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Enhancer Elements, Genetic
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Gene Expression
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Gene Knockdown Techniques
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Genetic Loci
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Genetic Predisposition to Disease*
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Genome-Wide Association Study
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Glioma / diagnosis
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Glioma / genetics*
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Glioma / metabolism
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Glioma / pathology
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Phenotype
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Polymorphism, Single Nucleotide
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Prognosis
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Risk
Substances
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Chromatin
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Intracellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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PHLDB1 protein, human
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Proto-Oncogene Proteins
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RNA, Small Interfering
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DDX6 protein, human
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DEAD-box RNA Helicases