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  • 1
    Keywords: brain ; CELLS ; tumor ; Germany ; PATHWAY ; PATHWAYS ; CLASSIFICATION ; SYSTEM ; SYSTEMS ; GENE ; GENES ; TUMORS ; PATIENT ; MECHANISM ; CONTRAST ; mechanisms ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; VARIANTS ; IDENTIFICATION ; LESIONS ; WHITE-MATTER ; SERIES ; pathology ; NEOPLASTIC TRANSFORMATION ; molecular ; VARIANT ; MUTATIONAL ANALYSIS ; ALLELES ; DYSPLASIA ; epilepsy ; focal cortical dysplasia ; FOCAL EPILEPSIES ; GANGLIOGLIOMAS ; glio-neuronal lesion ; GLIONEURONAL TUMORS ; tuberous sclerosis ; TUBEROUS SCLEROSIS COMPLEX
    Abstract: Epilepsy-associated malformations of cortical development (MCDs) comprise a variety of dysplastic and neoplastic lesions of yet undetermined molecular pathology. Histopathologic similarities between MCDs and dysplastic brain lesions in the autosomal inherited neurocutaneous phacomatosis tuberous sclerosis (TSC), which affects the TSC1 and/or TSC2 genes, suggest common pathogenetic mechanisms. Previous studies revealed different alterations of TSC1 and TSC2 in epilepsy-associated malformations and glio-neuronal tumors despite histopathologic similarities. In order to examine current clinico-pathologic classification systems of cortical malformations on the molecular level, we carried out a mutational analysis of TSC1 and TSC2 in a series of surgical specimens obtained from patients with FCD without Taylor type balloon cells (FCDIIa; n = 20), architectural dysplasias (FCDI; n = 15), nodular cortical heterotopias (NCH; It = 4), and heterotopic white matter neurons (WMNH; It = 19). In FCDIIa, abundant genomic polymorphisms were detected in TSC2 (intron 4) but no allelic variants observed in exon 17 of TSCL This allelic distribution pattern is in contrast to findings in FCDI and WMNH but also to those previously reported in FCDIIb (Taylor's balloon cell type). The latter revealed increased frequencies of specific alleles only in TSCL The determination of characteristic molecular genetic alterations in specific epilepsy-associated malformations will support a comprehensive clinico-pathologic classification system and help to identify molecular pathways with potential pathogenetic relevance. Our work is supported by DFG (SFB TRB [AJB], DFG B1 42 1/1-1 [113]), BONFOR, and Deutsche Krebshilfe
    Type of Publication: Journal article published
    PubMed ID: 16042315
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  • 2
    Keywords: APOPTOSIS ; EXPRESSION ; SURVIVAL ; CELL ; Germany ; PATHWAY ; SYSTEM ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; MEMBER ; TARGET ; NERVOUS-SYSTEM ; LYMPHOMA ; gene expression ; FACTOR-KAPPA-B ; RT-PCR ; CENTRAL-NERVOUS-SYSTEM ; NF-kappa B ; TARGETS ; pathology ; fluorescence in situ hybridization ; signaling ; FAMILIES ; CELL LYMPHOMA ; LEVEL ; NUCLEAR ; USA ; B-CELL ; germinal center ; central nervous system ; quantitative ; nuclear factor-kappa B ; primary central nervous system lymphomas (PCNSL)
    Abstract: Recent studies point to a role of nuclear factor (NF)-kappa B signaling in a subset of diffuse large B cell lymphomas. We have analyzed the expression of 21 genes encoding NF-kappa B family members, upstream modulators, and targets in 32 primary central nervous system lymphomas (PCNSLs) by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Compared with nonmalignant germinal center centroblasts, expression of BCL10, REL, IAP1, and TRAF1 was significantly lower in PCNSLs, whereas that of BAX, BCLXL, BCL2, MALT1, CARD9, CARD10, CARD11, CARD14, CCND2, cFLIP, RELA, RELB, NFKB1, NFK82, and IRF4 was higher. Hierarchical clustering of gene expression data revealed two distinct subgroups of PCNSLs, which were characterized by significantly different transcriptional levels, predominantly of BCL10, but also of REL and IAPI. Thus, these quantitative RT-PCR data with expression of genes of the NF-kappa B family as well as NF-kappa B-regulated genes together with immunohistochemical detection of nuclear RELA and REL indicate activation of the NF-kappa B pathway in PCNSLs, which may contribute to their high proliferative activity and the low level of apoptosis
    Type of Publication: Journal article published
    PubMed ID: 17356384
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  • 3
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; SYSTEM ; GENE ; PROTEIN ; DIFFERENTIATION ; primary ; DOMAIN ; MATURATION ; NERVOUS-SYSTEM ; IDENTIFICATION ; LYMPHOMA ; PLASMA ; MUTATION ; inactivation ; LYMPHOCYTES ; MUTATIONS ; PHENOTYPE ; CENTRAL-NERVOUS-SYSTEM ; SERIES ; B-CELL LYMPHOMA ; protein expression ; molecular ; FEATURES ; PATTERN ; TUMOR-SUPPRESSOR ; diffuse large B-cell lymphoma ; REPRESSOR ; SUPPRESSOR ; USA ; B-CELL LYMPHOMAS ; PCNSL ; B-CELL ; central nervous system ; systemic ; tumor suppressor ; BLIMP-1 ; BLIMP1 ; PRDM1 ; PRDM1/BLIMP-1 ; primary central nervous system lymphoma
    Abstract: Primary lympbomas of the CNS (PCNSLs) show molecular features of the late germinal center exit B-cell phenotype and are impaired in their terminal differentiation as indicated by a lack of immunoglobulin class switching. Because the positive regulatory domain I protein with ZNF domain (PRDM1/BLIMP1) is a master regulator of terminal B-cell differentiation into plasma cells, we investigated a series of 21 PCNSLs for the presence of mutations in the PRDM1 gene and alterations in the expression pattern of the PRDM1 protein. Direct sequencing of all coding exons of the PRDM1 gene identified deleterious mutations associated with abrogation of PRDM1 protein expression in 4 of 21 (19%) PCNSLs. Thus, similar to systemic diffuse large B-cell lymphomas, PRDM1 may be a tumor suppressor in some PCNSL and contribute to lymphomagenesis by impairing terminal differentiation
    Type of Publication: Journal article published
    PubMed ID: 18596541
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  • 4
    Keywords: CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; SYSTEM ; GENE ; GENE-EXPRESSION ; PROTEIN ; transcription ; PATIENT ; MECHANISM ; TRANSCRIPTION FACTOR ; cell signaling ; prognosis ; mechanisms ; NERVOUS-SYSTEM ; immunohistochemistry ; LYMPHOMA ; gene expression ; B-CELLS ; CENTRAL-NERVOUS-SYSTEM ; pathology ; OVEREXPRESSION ; POOR-PROGNOSIS ; B-CELL LYMPHOMA ; signaling ; SUBSET ; regulation ; diffuse large B-cell lymphoma ; USA ; outcome ; DLBCL ; primary central nervous system lymphoma ; gene expression analysis ; 3 ; TRANSCRIPTION-FACTOR ; Forkhead box P1
    Abstract: Forkhead box PI (FOXP1) protein is a transcription factor involved in cell signaling and regulation of gene expression. The overexpression of FOXP1 in a subgroup of systemic diffuse large B-cell lymphomas has been associated with an exceptionally poor clinical outcome. Data on FOXP1 expression in primary central nervous system lymphomas (PCNSL), that is, diffuse large B-cell lymphomas confined to the central nervous system, are not yet available. We analyzed 43 PCNSL from immunocompetent patients. Immunohistochemistry showed expression of FOXP1 protein in 21 (88%) of 24 cases. All 19 PCNSL analyzed by quantitative gene expression analysis showed overexpression of truncated FOXP1 Isoforms 3 and 9 and downregulation of normal-size FOXP1 compared with nonmalignant germinal center B cells, the normal counterpart of PCNSL tumor cells. Thus, truncated FOXP1 isoforms are preferentially overexpressed in PCNSL as they are in diffuse large B-cell lymphomas. Although the mechanisms are presently unclear, this overexpression may contribute to a poor prognosis in PCNSL
    Type of Publication: Journal article published
    PubMed ID: 19680146
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