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  • 1
    Keywords: ANGIOGENESIS ; CELLS ; EXPRESSION ; ENDOTHELIAL GROWTH-FACTOR ; INHIBITION ; POPULATION ; PROTEIN ; mechanisms ; DOWN-REGULATION ; HYPERMETHYLATION ; MALIGNANT GLIOMAS ; astrocytoma ; SUBTYPES ; PROMOTER METHYLATION ; GLIOBLASTOMA ; AKAP12 ; Gravin ; SSeCKS ; SSECKS/GRAVIN/AKAP12
    Abstract: The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression. We further performed quantitative methylation analysis of the AKAP12 promoter by MassARRAY (R) of normal brain, World Health Organization (WHO) grade I to IV astrocytomas, and glioma cell lines. Our results show that AKAP12 is expressed in a perivascular distribution in normal CNS, strongly upregulated in tumor cells in pilocytic astrocytomas, and weakly expressed in diffuse astrocytomas of WHO grade II to IV. Methylation analyses revealed specific hypermethylation of AKAP12 alpha promoter in WHO grade II to IV astrocytomas. Restoration experiments using 5-aza-2'-deoxycytidine in primary glioblastoma cells decreased AKAP12 alpha promoter methylation and markedly increased AKAP12 alpha mRNA levels. In summary, we demonstrate that AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. Our results further indicate that epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas; however, a tumor suppressive role of AKAP12 in distinct astrocytoma subtypes remains to be determined
    Type of Publication: Journal article published
    PubMed ID: 24042196
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  • 2
    Keywords: brain ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; SYSTEM ; DISEASE ; PROTEIN ; DIFFERENTIATION ; SURGERY ; MARKER ; antibodies ; antibody ; LESIONS ; MUTATION ; etiology ; MARKERS ; p53 ; MUTATIONS ; vimentin ; CENTRAL-NERVOUS-SYSTEM ; FREQUENT ; sensitivity ; pathology ; GLIOMAS ; GLIOMA ; GFAP ; SPECIMENS ; GLIOBLASTOMA ; IMMUNOREACTIVITY ; IDH1 ; ASTROCYTES ; HUMAN-BRAIN-TUMORS ; GLIOBLASTOMAS ; P53 EXPRESSION ; IDH1 mutation ; PANEL ; mIDH1R132H ; NEUROPATHOLOGY ; NOGO-A EXPRESSION ; reactive gliosis ; WT1
    Abstract: Differentiation of gliomas and reactive gliosis may be challenging both at primary tumor occurrence and at posttherapy biopsy. The most frequent IDH1 mutation found in the majority of WHO grade II and III gliomas can be visualized with an antibody specifically detecting mutant IDH1(R132H) protein. In this study, mIDH1R132H immunoreactivity in 120 reactive gliosis specimens of various etiologies is compared with Wilms Tumor 1 (WT1) and p53 expression, both markers applied for the differentiation of reactive gliosis and glioma. Although WT1 and p53 positive glial cells were found in 17% and 63% of cases respectively, all samples were negative for mIDH1R132H. Furthermore, we investigated 19 posttherapy gliomas ( 6 WHO II, 13 WHO III) with extensive reactive changes and detected mIDH1R132H positive cells in 13 specimens. In 5 of these cases, tumor cells were missed by conventional staining, showing the improved sensitivity of mIDH1R132H. Thus, mIDH1R132H is a tumor-specific marker that is superior to other established markers to differentiate reactive from neoplastic cells in grade II and III gliomas and allows identifying tumor cells in posttherapy specimens with extensive reactive changes. As IDH mutations are not characteristic of grade IV primary glioblastomas, this antibody cannot differentiate primary glioblastoma from reactive gliosis. Thus, caution has to be taken and a combined panel with other markers is needed
    Type of Publication: Journal article published
    PubMed ID: 20661018
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