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Cellular and Molecular Life Sciences :... Jun 2012Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for... (Review)
Review
Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions.
Topics: Animals; Astrocytoma; Disease Models, Animal; Gene Fusion; Humans; MAP Kinase Signaling System; Mice; Models, Genetic; Neurofibromin 1; Proto-Oncogene Proteins B-raf
PubMed: 22159586
DOI: 10.1007/s00018-011-0898-9 -
Indian Journal of Pathology &... May 2022The newest revision of the WHO classification of tumors of the central nervous system, also known as WHO 5 edition, introduces substantial changes, especially within the... (Review)
Review
The newest revision of the WHO classification of tumors of the central nervous system, also known as WHO 5 edition, introduces substantial changes, especially within the glial tumor category and separates adult-type and pediatric-type glial tumors into different categories for the first time. In addition, another category of glial tumors, "Circumscribed Astrocytic Gliomas" were also created. This group includes pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, astroblastoma, and the highly nebulous novel entity high-grade astrocytoma with piloid features. We present a brief and critical review of the pathological and molecular characteristics of these often well-demarcated tumors that can occur in adults as well as in the pediatric population.
Topics: Adult; Astrocytoma; Brain Neoplasms; Child; Glioma; Humans; Precancerous Conditions; World Health Organization
PubMed: 35562132
DOI: 10.4103/ijpm.ijpm_1019_21 -
Deutsches Arzteblatt International Nov 2010Primary brain tumors are among the ten most common causes of cancer-related death. There is no screening test for them, but timely diagnosis and treatment improve the... (Review)
Review
BACKGROUND
Primary brain tumors are among the ten most common causes of cancer-related death. There is no screening test for them, but timely diagnosis and treatment improve the outcome. Ideally, treatment should be provided in a highly specialized center, but patients reach such centers only on the referral of their primary care physicians or other medical specialists from a wide variety of fields. An up-to-date account of basic knowledge in this area would thus seem desirable, as recent years have seen major developments both in the scientific understanding of these tumors and in clinical methods of diagnosis and treatment.
METHODS
Selective search of the pertinent literature (PubMed and Cochrane Library), including the guidelines of the German Societies of Neurosurgery, Neurology, and Radiotherapy.
RESULTS AND CONCLUSION
Modern neuroradiological imaging, in particular magnetic resonance imaging, can show structural lesions at high resolution and provide a variety of biological and functional information, yet it is still no substitute for histological diagnosis. Gross total resection of gliomas significantly improves overall survival. New molecular markers can be used for prognostication. Chemotherapy plays a major role in the treatment of various different kinds of glioma. The median survival, however, generally remains poor, e.g., 14.6 months for glio-blastoma.
Topics: Adult; Aged; Astrocytoma; Brain; Brain Neoplasms; Cell Movement; Child; Combined Modality Therapy; Cross-Sectional Studies; Disease Progression; Female; Glioblastoma; Glioma; Humans; Male; Middle Aged; Neoplasm Invasiveness; Prognosis; Survival Analysis
PubMed: 21124703
DOI: 10.3238/arztebl.2010.0799 -
Folia Neuropathologica 2016Pilocytic astrocytomas (PAs) are the most frequent primary astroglial tumours affecting children and adolescents. They occur sporadically or in association with a... (Review)
Review
Pilocytic astrocytomas (PAs) are the most frequent primary astroglial tumours affecting children and adolescents. They occur sporadically or in association with a genetically determined syndrome - neurofibromatosis type 1. Classic PA usually manifests as a well-circumscribed, often cystic, slowly growing tumour, which corresponds to WHO grade I. The majority of pilocytic tumours arise along the neuraxis, predominantly in the cerebellum. They are associated with favourable long-term outcome or spontaneous regression, even after incomplete resection. However, the behaviour and prognosis might also be related to tumour histology and location. Pilomyxoid astrocytoma (PMA) represents a variant of classical PA with more invasive growth and increased risk of recurrences and dissemination. Typically, PAs exhibit distinct histology with biphasic architecture of loose, microcystic and compact, fibrillary areas. However, some tumours arise in an uncommon location and display heterogeneous histopathological appearance. The morphological pattern of PA can mimic some other glial neoplasms, including oligodendroglioma, pleomorphic xanthoastrocytoma, ependymoma or diffuse astrocytoma. Not infrequently, the advanced degenerative changes, including vascular fibrosis, and recent and old haemorrhages, may mimic vascular pathology. Sometimes, the neoplastic piloid tissue can resemble reactive gliosis, related to long-standing non neoplastic lesions. Not infrequently, PA exhibits histological features typical for anaplasia, including necrosis, mitoses and glomeruloid vascular proliferation that can suggest a diffuse high-grade glioma. However, even those PAs that lack distinct histological features of anaplasia can behave unpredictably, in a more aggressive manner, with leptomeningeal spreading. Genetic alterations resulting in aberrant signalling of the mitogen-activated protein kinase (MAPK) pathway have been considered to underlie the development of PAs. The most commonly identified KIAA1549-BRAF fusion is important for appropriate tumour molecular diagnosis. In this paper we summarize the clinicopathological presentation of PAs, with emphasis on their heterogeneous morphology, based on our own experience in the field of surgical neuropathology and the literature data. Diagnosis of pilocytic tumours requires careful analysis of clinical, histopathological and molecular features to avoid misinterpretation of these benign neoplastic lesions.
Topics: Animals; Astrocytes; Astrocytoma; Brain Neoplasms; Glioma; Humans; Mitogen-Activated Protein Kinases; Neoplasm Recurrence, Local
PubMed: 27764513
DOI: 10.5114/fn.2016.62530 -
Oncogene Apr 2021Adult pilocytic astrocytomas (PAs) have been regarded as indistinguishable from pediatric PAs in terms of genome-wide expression and methylation patterns. It has been...
Adult pilocytic astrocytomas (PAs) have been regarded as indistinguishable from pediatric PAs in terms of genome-wide expression and methylation patterns. It has been unclear whether adult PAs arise early in life and remain asymptomatic until adulthood, or whether they develop during adulthood. We sought to determine the age and origin of adult human PAs using two types of "marks" in the genomic DNA. First, we analyzed the DNA methylation patterns of adult and pediatric PAs to distinguish between PAs of different anatomic locations (n = 257 PA and control brain tissues). Second, we measured the concentration of nuclear bomb test-derived C in genomic DNA (n = 14 cases), which indicates the time point of the formation of human cell populations. Our data suggest that adult and pediatric PAs developing in the infratentorial brain are closely related and potentially develop from precursor cells early in life, whereas supratentorial PAs might show age and location-specific differences.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Astrocytoma; Child; Child, Preschool; Humans; Incidence; Infant; Infant, Newborn; Middle Aged; Young Adult
PubMed: 33731860
DOI: 10.1038/s41388-021-01738-0 -
Annual Review of Pathology Jan 2013Pediatric low-grade astrocytomas are the most common brain tumors in children. They can have similar microscopic and clinical features, making accurate diagnosis... (Review)
Review
Pediatric low-grade astrocytomas are the most common brain tumors in children. They can have similar microscopic and clinical features, making accurate diagnosis difficult. For patients whose tumors are in locations that do not permit full resection, or those with an intrinsically aggressive biology, more effective therapies are required. Until recently, little was known about the molecular changes that drive the initiation and growth of pilocytic and other low-grade astrocytomas beyond the association of a minority of cases, primarily in the optic nerve, with neurofibromatosis type 1. Over the past several years, a wide range of studies have implicated the BRAF oncogene and other members of this signaling cascade in the pathobiology of pediatric low-grade astrocytoma. In this review, we attempt to summarize this rapidly developing field and discuss the potential for translating our growing molecular knowledge into improved diagnostic and prognostic biomarkers and new targeted therapies.
Topics: Animals; Astrocytoma; Brain Neoplasms; Humans; Neoplasm Grading
PubMed: 23121055
DOI: 10.1146/annurev-pathol-020712-164009 -
Oncotarget Oct 2015Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and... (Comparative Study)
Comparative Study
Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.
Topics: Adult; Age Factors; Aneuploidy; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Child; Cohort Studies; Female; Gene Expression Profiling; Humans; Male; Mutation; Neoplasm Staging; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-mdm2; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 1; Reverse Transcriptase Polymerase Chain Reaction; Young Adult
PubMed: 26378811
DOI: 10.18632/oncotarget.5571 -
BMC Cancer Dec 2022Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein...
BACKGROUND
Juvenile Pilocytic Astrocytomas (JPAs) are one of the most common pediatric brain tumors, and they are driven by aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway. RAF-fusions are the most common genetic alterations identified in JPAs, with the prototypical KIAA1549-BRAF fusion leading to loss of BRAF's auto-inhibitory domain and subsequent constitutive kinase activation. JPAs are highly vascular and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. This can result in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq.
METHODS
To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level.
RESULTS
Integration of these datasets allowed the identification and detailed characterization of two novel BRAF fusion partners, PTPRZ1 and TOP2B, in addition to the canonical fusion with partner KIAA1549. Additionally, our Hi-C datasets enabled investigations of 3D genome architecture in JPAs which showed a high level of correlation in 3D compartment annotations between JPAs compared to other pediatric tumors, and high similarity to normal adult astrocytes. We detected interactions between BRAF and its fusion partners exclusively in tumor samples containing BRAF fusions.
CONCLUSIONS
We demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution. We suggest that linked-reads and Hi-C could be used in clinic for the detection and characterization of JPAs.
Topics: Child; Adult; Humans; Multiomics; Proto-Oncogene Proteins B-raf; Oncogene Proteins, Fusion; Astrocytoma; Brain Neoplasms; Receptor-Like Protein Tyrosine Phosphatases, Class 5
PubMed: 36503484
DOI: 10.1186/s12885-022-10359-z -
Neurobiology of Disease Jan 2016Glioblastoma (GBM, Grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults. Hypoxia is a distinct feature in GBM and... (Review)
Review
Glioblastoma (GBM, Grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults. Hypoxia is a distinct feature in GBM and plays a significant role in tumor progression, resistance to treatment and poor outcomes. This review considers the effects of hypoxia on astrocytic tumors and the mechanisms that contribute to tumor progression and therapeutic resistance, with a focus on the vascular changes, chemotaxic signaling pathways and metabolic alterations involved.
Topics: Animals; Astrocytoma; Brain Neoplasms; Humans; Hypoxia
PubMed: 26094595
DOI: 10.1016/j.nbd.2015.06.007 -
CNS Oncology Apr 2017Astrocytomas are responsible for 30% of all primitive intramedullary tumors with cervicothoracic predominance. However, only about one hundred cases of intramedullary... (Review)
Review
Astrocytomas are responsible for 30% of all primitive intramedullary tumors with cervicothoracic predominance. However, only about one hundred cases of intramedullary pilocytic astrocytomas were described. The authors described the case of a 69 year-old patient presenting with a broad-base gait, bilateral pain and dysesthesia of inferior limbs with a diagnosis of an intra-axial cystic lesion centered to the conus medullaris, diagnosed as pilocytic astrocytoma of conus medullaris (PACM) after surgery. To the best of our knowledge, only two previous reports concerning PACM were made. As benign lesions associated with long survivals, function should be the mainstay of treatment of PACM. Surgical resection should be performed. Adjuvant radiotherapy or chemotherapy has no establish role in pilocytic astrocytic lesions.
Topics: Aged; Astrocytoma; Female; Humans; Magnetic Resonance Imaging; Spinal Cord; Spinal Cord Neoplasms
PubMed: 28425761
DOI: 10.2217/cns-2016-0030