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Nature Communications Apr 2022Glioblastoma (GBM) is a deadly disease without effective treatment. Because glioblastoma stem cells (GSCs) contribute to tumor resistance and recurrence, improved...
Glioblastoma (GBM) is a deadly disease without effective treatment. Because glioblastoma stem cells (GSCs) contribute to tumor resistance and recurrence, improved treatment of GBM can be achieved by eliminating GSCs through inducing their differentiation. Prior efforts have been focused on studying GSC differentiation towards the astroglial lineage. However, regulation of GSC differentiation towards the neuronal and oligodendroglial lineages is largely unknown. To identify genes that control GSC differentiation to all three lineages, we performed an image-based genome-wide RNAi screen, in combination with single-cell RNA sequencing, and identified ZNF117 as a major regulator of GSC differentiation. Using patient-derived GSC cultures, we show that ZNF117 controls GSC differentiation towards the oligodendroglial lineage via the Notch pathway. We demonstrate that ZNF117 is a promising target for GSC differentiation therapy through targeted delivery of CRISPR/Cas9 gene-editing nanoparticles. Our study suggests a direction to improve GBM treatment through differentiation of GSCs towards various lineages.
Topics: Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Glioblastoma; Humans; Neoplastic Stem Cells
PubMed: 35459228
DOI: 10.1038/s41467-022-29884-3 -
CNS Oncology 2015Oligodendroglial tumors are chemosensitive with a favorable prognosis compared with other histological subtypes. The genetic hallmark of co-deletion of 1p and 19q... (Review)
Review
Oligodendroglial tumors are chemosensitive with a favorable prognosis compared with other histological subtypes. The genetic hallmark of co-deletion of 1p and 19q determines both treatment response and prognosis. While this test now forms part of routine histopathology diagnosis in many laboratories, alternative noninvasive imaging biomarkers of tumor genotype remain an attractive proposition. This review will focus on imaging biomarkers of molecular genetics in oligodendroglial tumors.
Topics: Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 9; Humans; Neuroimaging; Oligodendroglioma
PubMed: 26478219
DOI: 10.2217/cns.15.37 -
CNS Oncology 2015Oligodendroglioma (WHO Grade 2) and anaplastic oligodendroglioma (WHO Grade 3) are glial tumors composed of neoplastic cellular elements that resemble oligodendrocytes.... (Review)
Review
Oligodendroglioma (WHO Grade 2) and anaplastic oligodendroglioma (WHO Grade 3) are glial tumors composed of neoplastic cellular elements that resemble oligodendrocytes. The treatment of recurrent, alkylator refractory oligodendroglial tumors is challenging given the paucity of effective treatment and lack of randomized controlled trials on which to base therapy. Notwithstanding the lack of prospective, randomized data, treatment of oligodendroglial tumors with bevacizumab can be recommended tentatively recognizing that preliminary studies suggest efficacy. Somatic mutations of the isocitrate dehydrogenase enzymes (IDH1 and IDH2) appear to play a critical role in the pathogenesis of most oligodendroglial tumors and agents that target these mutations are a potential therapeutic option. Additionally, reversal of CpG island hypermethylated phenotype status through inhibition of DNA methyltransferase with an inhibitor such as decitabine may provide a target for future studies.
Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Humans; Isocitrate Dehydrogenase; Neoplasm Recurrence, Local; Oligodendroglioma; Vascular Endothelial Growth Factor A
PubMed: 26509217
DOI: 10.2217/cns.15.27 -
International Journal of Molecular... Jan 2009Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified... (Review)
Review
Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified according to the World Health Organization (WHO) classification of tumors of the nervous system. Over the past 20 years the cytogenetic and molecular genetic alterations associated with glioma formation and progression have been intensely studied and genetic profiles as additional aids to the definition of brain tumors have been incorporated in the WHO classification. In fact, first steps have been undertaken in supplementing classical histopathological diagnosis by the use of molecular tests, such as MGMT promoter hypermethylation in glioblastomas or detection of losses of chromosome arms 1p and 19q in oligodendroglial tumors. The tremendous progress that has been made in the use of array-based profiling techniques will likely contribute to a further molecular refinement of glioma classification and lead to the identification of glioma core pathways that can be specifically targeted by more individualized glioma therapies.
Topics: Animals; Biomarkers, Tumor; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Gene Expression Profiling; Glioma; Humans; Molecular Diagnostic Techniques; Tumor Suppressor Proteins
PubMed: 19333441
DOI: 10.3390/ijms10010184 -
Neuropathology : Official Journal of... Apr 2022We report a case of oligodendroglioma that had consistent histopathological features as well as a distinct change in 1p/19q status in the second recurrence, after...
We report a case of oligodendroglioma that had consistent histopathological features as well as a distinct change in 1p/19q status in the second recurrence, after temozolomide chemotherapy and radiotherapy. The first tumor recurrence had oligodendroglial morphology, IDH1 R132H and TERT promoter mutations, and 1p/19q codeletion detected by fluorescent in situ hybridization (FISH). Copy number analysis, assessed by next-generation sequencing, confirmed 1p/19q codeletion, and disclosed loss of heterozygosity (LOH) of chromosomes 4 and 9 and chromosome 11 gain. The second recurrence featured not only oligodendroglial morphology but also the appearance of admixed multinucleated giant cells or neoplastic cells having oval nuclei and mitoses and showing microvascular proliferation; it maintained IDH1 R132H and TERT promoter mutations, acquired TP53 mutation, and showed 19q LOH, but disomic 1p, detected by FISH. Copy number analysis depicted LOH of chromosomes 3p, 13, and 19q, 1p partial deletion (1p chr1p34.2-p11), and gain of chromosomes 2p25.3-p24.1, 8q12.2-q24.3, and 11q13.3-q25. B-allele frequency analysis of polymorphic sites disclosed copy-neutral LOH at 1p36.33-p34.2, supporting the initial deletion of 1p, followed by reduplication of 1p36.33-p34.2 alone. These findings suggest that the two tumor recurrences might have originated from an initial neoplastic clone, featuring 1p/19q codeletion and IDH1 and TERT promoter mutations, and have independently acquired other copy number alterations. The reduplication of chromosome 1p might be the result of temozolomide treatment, and gave rise to false negative 1p deletion detected by FISH. The possibility of 1p copy-neutral LOH should be considered in recurrent oligodendrogliomas with altered 1p/19q status detected by FISH.
Topics: Brain Neoplasms; Chromosome Aberrations; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Humans; In Situ Hybridization, Fluorescence; Isocitrate Dehydrogenase; Neoplasm Recurrence, Local; Oligodendroglioma; Temozolomide
PubMed: 35144313
DOI: 10.1111/neup.12789 -
Medicina (Kaunas, Lithuania) Jul 2019Being the fourth leading cause of cancer-related death, glial tumors are highly diverse tumor entities characterized by important heterogeneity regarding tumor... (Review)
Review
Being the fourth leading cause of cancer-related death, glial tumors are highly diverse tumor entities characterized by important heterogeneity regarding tumor malignancy and prognosis. However, despite the identification of important alterations in the genome of the glial tumors, there remains a gap in understanding the mechanisms involved in glioma malignancy. Previous research focused on decoding the genomic alterations in these tumors, but due to intricate cellular mechanisms, the genomic findings do not correlate with the functional proteins expressed at the cellular level. The development of mass spectrometry (MS) based proteomics allowed researchers to study proteins expressed at the cellular level or in serum that may provide new insights on the proteins involved in the proliferation, invasiveness, metastasis and resistance to therapy in glial tumors. The integration of data provided by genomic and proteomic approaches into clinical practice could allow for the identification of new predictive, diagnostic and prognostic biomarkers that will improve the clinical management of patients with glial tumors. This paper aims to provide an updated review of the recent proteomic findings, possible clinical applications, and future research perspectives in diffuse astrocytic and oligodendroglial tumors, pilocytic astrocytomas, and ependymomas.
Topics: Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Glioma; Humans; Mass Spectrometry; Neoplasm Staging; Neoplasms; Oligodendroglioma; Prognosis; Proteomics
PubMed: 31357616
DOI: 10.3390/medicina55080412 -
Advances in Anatomic Pathology Mar 2015Low-grade gliomas (LGG) constitute grades I and II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow... (Review)
Review
Low-grade gliomas (LGG) constitute grades I and II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow growing, they may be associated with significant morbidity and mortality because of recurrence and malignant progression, even in the setting of optimal resection. LGG in pediatric and adult age groups are currently classified by morphologic criteria. Recent years have heralded a molecular revolution in understanding brain tumors, including LGG. Next-generation sequencing has definitively demonstrated that pediatric and adult LGG fundamentally differ in their underlying molecular characteristics, despite being histologically similar. Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the mitogen-activated protein kinase signaling pathway. Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors. TERT promoter mutations are also noted in LGG and are mainly associated with oligodendrogliomas. These findings have considerably refined approaches to classifying these tumors. Moreover, many of the molecular alterations identified in LGG directly impact on prognosis, tumor biology, and the development of novel therapies.
Topics: Adult; Brain; Child; Glioma; Humans; Molecular Diagnostic Techniques
PubMed: 25664944
DOI: 10.1097/PAP.0000000000000049 -
Archives of Pathology & Laboratory... May 2011Gliomas are the most common primary brain tumors of adults and include a variety of histologic types and morphologies. Histologic evaluation remains the gold standard... (Review)
Review
CONTEXT
Gliomas are the most common primary brain tumors of adults and include a variety of histologic types and morphologies. Histologic evaluation remains the gold standard for glioma diagnosis; however, diagnostic difficulty may arise from tumor heterogeneity, overlapping morphologic features, and tumor sampling. Recently, our knowledge about the genetics of these tumors has expanded, and new molecular markers have been developed. Some of these markers have shown diagnostic value, whereas others are useful prognosticators for patient survival and therapeutic response.
OBJECTIVE
To review the most clinically useful molecular markers and their detection techniques in gliomas.
DATA SOURCES
Review of the pertinent literature and personal experience with the molecular testing in gliomas.
CONCLUSIONS
This article provides an overview of the most common molecular markers in neurooncology, including 1p/19q codeletion in oligodendroglial tumors, mutations in the isocitrate dehydrogenase 1 and 2 genes in diffuse gliomas, hypermethylation of the O(6)-methylguanine-DNA methyltransferase gene promoter in glioblastomas and anaplastic gliomas, alterations in the epidermal growth factor receptor and phosphatase and tensin homolog genes in high-grade gliomas, as well as BRAF alterations in pilocytic astrocytomas. Molecular testing of gliomas is increasingly used in routine clinical practice and requires that neuropathologists be familiar with these genetic markers and the molecular diagnostic techniques for their detection.
Topics: Biomarkers, Tumor; Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Glioma; Humans; Molecular Diagnostic Techniques; Mutation; Prognosis
PubMed: 21526954
DOI: 10.5858/2010-0649-RAIR.1 -
Clinical & Experimental Optometry Nov 2016Oligodendrogliomas are rare slow-growing asymptomatic glial tumours that usually present in patients in their fourth to sixth decades of life. Neurological symptoms that... (Review)
Review
Oligodendrogliomas are rare slow-growing asymptomatic glial tumours that usually present in patients in their fourth to sixth decades of life. Neurological symptoms that may present include nausea, headache, vomiting, diplopia, confusion, focal weakness, numbness and seizures. The treatment of oligodendroglioma tumours is based on functional status classification, lumbar puncture, imaging of the head, tumour biopsy and genetic testing. Grades II and IV oligodendroglial tumours, which have co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) and mutations in isocitrate dehydrogenase, have the most favourable prognosis, as they respond well to neurosurgery and chemotherapy. This report will discuss a general case of papilloedema in a young patient with oligodendroglioma and the role of the optometrist in its post-neurosurgical and chemotherapeutic care.
Topics: Adult; Brain Neoplasms; Humans; Magnetic Resonance Imaging; Male; Oligodendroglioma; Papilledema; Tomography, Optical Coherence; Visual Fields
PubMed: 27489047
DOI: 10.1111/cxo.12416 -
The British Journal of Radiology Dec 2011Despite advances in therapy, gliomas remain associated with poor prognosis. Clinical advances will be achieved through molecularly targeted biological therapies, for... (Review)
Review
Despite advances in therapy, gliomas remain associated with poor prognosis. Clinical advances will be achieved through molecularly targeted biological therapies, for which knowledge of molecular genetic and gene expression characteristics in relation to histopathology and in vivo imaging are essential. Recent research supports the molecular classification of gliomas based on genetic alterations or gene expression profiles, and imaging data supports the concept that molecular subtypes of glioma may be distinguished through non-invasive anatomical, physiological and metabolic imaging techniques, suggesting differences in the baseline biology of genetic subtypes of infiltrating glioma. Furthermore, MRI signatures are now being associated with complex gene expression profiles and cellular signalling pathways through genome-wide microarray studies using samples obtained by image guidance which may be co-registered with clinical imaging. In this review we describe the pathobiology, molecular pathogenesis, stem cells and imaging characteristics of gliomas with emphasis on astrocytomas and oligodendroglial neoplasms.
Topics: Adult; Animals; Astrocytoma; Brain Neoplasms; Breast; Child; Gene Expression Profiling; Glioma; Humans; Magnetic Resonance Imaging; Mice; Molecular Biology; Oligodendroglioma
PubMed: 22433833
DOI: 10.1259/bjr/23430927