Application of a BRAF V600E mutation-specific antibody for the diagnosis of hairy cell leukemia.

In recent times BRAF V600E mutations have emerged as a genetic hallmark of hairy cell leukemia (HCL). This specific point mutation is present in virtually all cases of HCL but is exceedingly rare in other peripheral B-cell neoplasms. In this study we investigated the application of a BRAF V600E mutation-specific antibody (clone VE1) to differentiate HCL from HCL mimics, such as HCL variant and splenic marginal zone lymphoma.

No prognostic value of IDH1 mutations in a series of 100 WHO grade II astrocytomas.

Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) have been identified in approximately 70-80 % of astrocytomas and oligodendrogliomas of WHO grades II and III, and in secondary glioblastomas. In addition, a low incidence of IDH2 mutations has been detected in these tumors, and the occurence of IDH1 and IDH2 mutations is mutually exclusive. For patients with anaplastic gliomas and glioblastomas with IDH1 mutations, overall survival was significantly longer than for patients with wild-type tumours.

Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling.

The dimerisation of Raf kinases involves a central cluster within the kinase domain, the dimer interface (DIF). Yet, the importance of the DIF for the signalling potential of wild-type B-Raf (B-Raf(wt)) and its oncogenic counterparts remains unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Raf(wt) and several of its gain-of-function (g-o-f) mutants.

Comparison of immunohistochemistry, DNA sequencing and allele-specific PCR for the detection of IDH1 mutations in gliomas.

Previous studies have identified mutations of the isocitrate dehydrogenase 1 (IDH1) gene in more than 70% of World Health Organization (WHO) grade II and III gliomas. The most frequent mutation leads to a specific amino acid change from arginine to histidine at codon 132 (c.395G>A, p.

Prognostic value of three different methods of MGMT promoter methylation analysis in a prospective trial on newly diagnosed glioblastoma.

Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O(6)-methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need.

Clinical neuropathology practice news 2-2012: BRAF V600E testing.

Activating mutations of the serine threonine kinase v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), most commonly of the V600E type, are found in a wide range of human neoplasms including primary and secondary brain tumors. Therapeutic BRAF inhibitors have shown clinically meaningful activity, particularly in metastatic BRAF V600E mutated melanoma including patients with brain metastases. Therefore, in current neuropathological practice BRAF testing is of clinical importance in tissue samples of melanoma brain metastases in order to identify cases amenable to therapy with BRAF inhibitors.

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples.

Epigenetically mediated downregulation of the differentiation-promoting chaperon protein CRABP2 in astrocytic gliomas.

Impairment of endogenous differentiation pathways like retinoic acid (RA) signaling seems to be a central pathogenetic event in astrocytic gliomas. Among others, expression of the differentiation-promoting RA chaperon protein cellular retinoic acid binding protein 2 (CRABP2) is extenuated in high-grade gliomas. Against this background, we aimed at identifying potential pathomechanisms underlying reduced CRABP2 expression in these tumors.

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide.

IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom.

Introduction: Seizures are the most common initial symptom in patients with low-grade glioma and their occurrence strongly depends on the tumor location. The majority of low-grade gliomas reveal mutations in the genes encoding isocitrate-dehydrogenase 1 (IDH1) or 2 (IDH2). These mutations are associated with metabolic changes that are potentially epileptogenic.

Brain metastases: pathobiology and emerging targeted therapies.

Brain metastases (BM) are common in cancer patients and are associated with high morbidity and poor prognosis, even after intensive multimodal therapy including resection, radiotherapy (stereotactic radiosurgery or whole brain radiotherapy) and chemotherapy. However, advances in the understanding of the pathobiology of BM and the development of molecular targeted agents hold promise for improved prophylaxis and therapy of BM. Here we provide a comprehensive review of the current concepts on mechanisms of the brain-metastatic cascade involving hematogenous dissemination of tumor cells, attachment to microvessel endothelial cells, extravasation into the brain, interaction with the local microenvironment, angiogenesis and intraparenchymal proliferation.

Biological and clinical heterogeneity of MYCN-amplified medulloblastoma.

Focal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB).

Addressing diffuse glioma as a systemic brain disease with single-cell analysis.

Objective: To analyze infiltration patterns of IDH1 mutant diffuse gliomas into the brain by identification of single tumor cells applying an antibody specific to mutant IDH1 R132H protein.

Design: Immunohistochemical analysis.

Setting: University hospital.

The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis.

Malignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt-specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas.

Long-term outcome after radiotherapy in patients with atypical and malignant meningiomas--clinical results in 85 patients treated in a single institution leading to optimized guidelines for early radiation therapy.

Purpose: Previously, we could show that the new World Health Organization (WHO) classification of meningiomas significantly correlated with outcome in patients with atypical and anaplastic histology. In the present work, we analyzed our long-term experience in radiotherapy for atypical and malignant meningioma diagnosed according to the most recent WHO categorization system.

Patients And Methods: Sixty-two patients with atypical and 23 patients with malignant meningioma have been treated with radiotherapy.

Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases.

Brain metastases (BM) are frequent and carry a dismal prognosis. BRAF V600E mutations are found in a broad range of tumor types and specific inhibitors targeting BRAF V600E protein exist. We analyzed tumoral BRAF V600E-mutant protein expression using the novel mutation-specific antibody VE1 in a series of 1,120 tumor specimens (885 BM, 157 primary tumors, 78 extra-cranial metastases) of 874 BM patients.

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology.

2-Hydroxyglutarate concentration in serum from patients with gliomas does not correlate with IDH1/2 mutation status or tumor size.

IDH1/2 mutations occur at high frequency in diffusely infiltrating gliomas of the WHO grades II and III and were identified as a strong prognostic marker in all WHO grades of gliomas. Mutated IDH1 or IDH2 protein leads to the generation of excessive amounts of the metabolite 2-hydroxyglutarate (2HG) in tumor cells. Here, we evaluated whether 2HG levels in preoperative serum samples from patients with gliomas correlate with the IDH1/2 mutation status and whether there is an association between 2HG levels and glioma size.

FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma.

Purpose: Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to identify molecular biomarkers that will allow early and effective treatment stratification in these non-WNT/non-SHH tumors.

Patients And Methods: We combined transcriptome and DNA copy-number analyses for 64 primary medulloblastomas.

Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: one step forward, and one step back?

A group of 160 patients with primary glioblastoma treated with radiotherapy and temozolomide was analyzed for the impact of O6-methly-guanly-methyl-transferase (MGMT)-promoter methylation as well as isocitrate dehydrogenase (IDH)1-mutational status. Unexpectedly, overall survival or progression-free survival were not longer in the group with methylated MGMT-promoter as compared to patients without that methylation. IDH-1 mutations were significantly associated with increased overall survival.

A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat.

Incompletely resectable ependymomas are associated with poor prognosis despite intensive radio- and chemotherapy. Novel treatments have been difficult to develop due to the lack of appropriate models. Here, we report on the generation of a high-risk cytogenetic group 3 and molecular group C ependymoma model (DKFZ-EP1NS) which is based on primary ependymoma cells obtained from a patient with metastatic disease.

Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients.

The p53 tumor suppressor is stabilized by inhibitor of growth 1 (ING1) by blocking polyubiquitination.

The INhibitor of Growth tumor suppressors (ING1-ING5) affect aging, apoptosis, DNA repair and tumorigenesis. Plant homeodomains (PHD) of ING proteins bind histones in a methylation-sensitive manner to regulate chromatin structure. ING1 and ING2 contain a polybasic region (PBR) adjacent to their PHDs that binds stress-inducible phosphatidylinositol monophosphate (PtIn-MP) signaling lipids to activate these INGs.

Immunohistochemical analysis of 1844 human epithelial and haematopoietic tumours and sarcomas for IDH1R132H mutation.

Aims: Mutations in the isocitrate dehydrogenase 1 gene have been identified recently to play a key role in diffuse astrocytoma and oligodendroglioma as well as in acute myeloid leukaemia. In glioma, IDH1R132H is the most common mutation type, which is associated with younger patient age and longer patient survival compared to wild-type status. Sequencing analyses of carcinomas and lymphomas have detected IDH1 mutations in only a small fraction of cases.