Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in various developmental pathways are common themes in cancer. The early B-cell factors (EBF) are a family of four highly conserved DNA-binding transcription factors with an atypical zinc-finger and helix-loop-helix motif. They are involved in the differentiation and maturation of several cell lineages including B-progenitor lymphoblasts, neuronal precursors, and osteoblast progenitors. During B-cell development, EBF1 is required for the expression of Pax5, an essential factor for the production of antibody-secreting cells. Accumulating evidence indicates that genomic deletion of the EBF1 gene contributes to the pathogenesis, drug resistance, and relapse of B-progenitor acute lymphoblastic leukemia (ALL). Epigenetic silencing and genomic deletion of the EBF3 locus in chromosome 10q are very frequent in glioblastoma (GBM). Strikingly, the frequency of EBF3 loss in GBM is similar to that of the loss of Pten, a key suppressor of gliomagenesis. Cancer-specific somatic mutations were detected in EBF3 in GBM and in both EBF1 and EBF3 in pancreatic ductal adenocarcinoma. These missense mutations occur in the DNA-binding domain or the conserved IPT/TIG domain, suggesting that they might disrupt the functions of these two proteins. Functional studies revealed that EBF3 represses the expression of genes required for cell proliferation [e.g., cyclins and cyclin-dependent kinases (CDK)] and survival (e.g., Mcl-1 and Daxx) but activates those involved in cell cycle arrest (e.g., p21 and p27), leading to growth suppression and apoptosis. Therefore, EBFs represent new tumor suppressors whose inactivation blocks normal development and contributes to tumorigenesis of diverse types of human cancer.
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PMID:Emerging roles of the EBF family of transcription factors in tumor suppression. 1999 7

Metastable epialleles (MEs) are mammalian genomic loci where epigenetic patterning occurs before gastrulation in a stochastic fashion leading to systematic interindividual variation within one species. Importantly, periconceptual nutritional influences may modulate the establishment of epigenetic changes, such as DNA methylation at MEs. Based on these characteristics, we exploited Infinium HumanMethylation450 BeadChip kits in a 2-tissue parallel screen on peripheral blood leukocyte and colonic mucosal DNA from 10 children without identifiable large intestinal disease. This approach led to the delineation of 1776 CpG sites meeting our criteria for MEs, which associated with 1013 genes. The list of ME candidates exhibited overlaps with recently identified human genes (including CYP2E1 and MGMT, where methylation has been associated with Parkinson disease and glioblastoma, respectively) in which perinatal DNA methylation levels where linked to maternal periconceptual nutrition. One hundred 18 (11.6%) of the ME candidates overlapped with genes where DNA methylation correlated (r > 0.871; p < 0.055) with expression in the colon mucosa of 5 independent control children. Genes involved in homophilic cell adhesion (including cadherin-associated genes) and developmental processes were significantly overrepresented in association with MEs. Additional filtering of gene expression-correlated MEs defined 35 genes, associated with 2 or more CpG sites within a 10 kb genomic region, fulfilling the ME criteria. DNA methylation changes at a number of these genes have been linked to various forms of human disease, including cancers, such as asthma and acute myeloid leukemia (ALOX12), gastric cancer (EBF3), breast cancer (NAV1), colon cancer and acute lymphoid leukemia (KCNK15), Wilms tumor (protocadherin gene cluster; PCDHAs) and colorectal cancer (TCERG1L), suggesting a potential etiologic role for MEs in tumorigenesis and underscoring the possible developmental origins of these malignancies. The presented compendium of ME candidates may accelerate our understanding of the epigenetic origins of common human disorders.
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PMID:Human metastable epiallele candidates link to common disorders. 2332 99