Acta neuropathologica communications
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Acta Neuropathol Commun · Apr 2016
TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy.
Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. ⋯ MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS.
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Acta Neuropathol Commun · Dec 2015
PI3 kinase mutations and mutational load as poor prognostic markers in diffuse glioma patients.
Recent advances in molecular diagnostics allow diffuse gliomas to be classified based on their genetic changes into distinct prognostic subtypes. However, a systematic analysis of all molecular markers has thus far not been performed; most classification schemes use a predefined and select set of genes/molecular markers. Here, we have analysed the TCGA dataset (combined glioblastoma (GBM) and lower grade glioma (LGG) datasets) to identify all prognostic genetic markers in diffuse gliomas in order to generate a comprehensive classification scheme. ⋯ We have identified PI3K mutations as novel prognostic markers in gliomas. We also demonstrate that the mutational load is associated with tumor grade. The increase in mutational load may partially explain the increased aggressiveness of higher grade diffuse gliomas when a subset of the affected genes actively contributes to gliomagenesis and/or progression.
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Acta Neuropathol Commun · Jun 2015
DNA copy number analysis of Grade II-III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status.
Isocitrate dehydrogenase (IDH) mutation status and grade define subgroups of diffuse gliomas differing based on age, tumor location, presentation, and prognosis. While some biologic differences between IDH mutated (IDH (mut)) and wild-type (IDH (wt)) gliomas are clear, the distinct alterations associated with progression of the two subtypes to glioblastoma (GBM, Grade IV) have not been well described. We analyzed copy number alterations (CNAs) across grades (Grade II-III and GBM) in both IDH (mut) and IDH (wt) infiltrating gliomas using molecular inversion probe arrays. ⋯ Taken together, these analyses demonstrate distinct molecular ontogeny between IDH (wt) and IDH (mut) gliomas. Our data also support the novel findings that malignant progression of IDH (mut) gliomas to GBM involves increased genomic instability and genomic catastrophe, while IDH (wt) lower grade tumors are virtually identical to GBMs at the level of DNA copy number alterations.
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Acta Neuropathol Commun · Oct 2014
The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease.
Variably protease sensitive prionopathy (VPSPr) is a recently described, sporadic human prion disease that is pathologically and biochemically distinct from the currently recognised sporadic Creutzfeldt-Jakob disease (sCJD) subtypes. The defining biochemical features of the abnormal form of the prion protein (PrPSc) in VPSPr are increased sensitivity to proteolysis and the presence of an N- and C-terminally cleaved ~8 kDa protease resistant PrPSc (PrPres) fragment. The biochemical and neuropathological profile of VPSPr has been proposed to resemble either Gerstmann-Sträussler-Scheinker syndrome (GSS) or familial CJD with the PRNP-V180I mutation. However, in some cases of VPSPr two protease resistant bands have been observed in Western blots that co-migrate with those of type 2 PrPres, suggesting that a proportion of the PrPSc present in VPSPr has properties similar to those of sCJD. ⋯ Therefore, PrPSc in VPSPr is heterogeneous in terms of protease sensitivity and stability to denaturation with the chaotrope GdnHCl and includes a proportion with similar properties to that found in sCJD.
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Acta Neuropathol Commun · Oct 2014
Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer's disease.
The accumulation of neurofibrillary tangles in Alzheimer's disease (AD) propagates with characteristic spatiotemporal patterns which follow brain network connections, implying trans-synaptic transmission of tauopathy. Since misfolded tau has been shown to transmit across synapses in AD animal models, we hypothesized that synapses in AD patients may contain misfolded tau. By immunofluorescence imaging of bipartite synapses from AD subjects, we detected tau protein in 38.4% of presynaptic and 50.9% of postsynaptic terminals. ⋯ Non-demented elderly also showed considerable synaptic tau hyperphosphorylation and some misfolding, implicating the synapse as one of the first subcellular compartments affected by tauopathy. Misfolding of tau protein appeared to occur in situ inside synaptic terminals, without mislocalizing or mistrafficking. Misfolded tau at synapses may represent early signs of neuronal degeneration, mediators of synaptotoxicity, and anatomical substrates for transmitting tauopathy, but its actual role in these processes remain to be elucidated.