title: Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility.
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.
authors.affiliation: Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Baskin
authors.affiliation: Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.|Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Woods
authors.affiliation: Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Mendoza-Fandiño
authors.affiliation: Department of Neuro-oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Forsyth
authors.affiliation: Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Egan
authors.affiliation: Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
mesh_terms: D000483:Alleles; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11; D019295:Computational Biology; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005910:Glioma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012306:Risk
chemical_list: D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C487973:PHLDB1 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C094683:DDX6 protein, human; D053487:DEAD-box RNA Helicases