Braf gene duplication constitutes a mechanism of mapk pathway. A pilocytic astrocytoma and its variant juvenile pilomyxoid astrocytoma is a brain tumor that occurs more often in children and young adults in the first 20 years of life. Pilocytic astrocytoma is the most common childhood brain tumor, characterized by constitutive mapk activation. Approaches based on constitutive mapk activation were pursued to model human brain tumors in mice 1012. The term pilocytic to describe astrocytoma variants has been used since the 1930s 8, 18 to indicate cells with hairlike, bipolar processes. Mapk pathway activation in pilocytic astrocytoma springerlink. Health, general genetic aspects extracellular signalregulated kinases research gliomas oncogenes tumors.
As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Histology was remarkable for a lowgrade glioma composed of mildly atypical astrocytes with piloid. Today, what we call pilocytic astrocytoma pa has had a number of names before the who classification system became generally accepted. A recurrent feature of pa is deregulation of the mitogen activated protein kinase mapk pathway most often through kiaa1549braf fusion, but also by other braf or raf1gene. Pilocytic astrocytoma pa is a world health organization who grade i neoplasm with an expected benign course following surgical resection and a 10year survival rate of more than 95%. Pilocytic astrocytoma pa is the most common tumor of the pediatric. Korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Mapk pathway activation in pilocytic astrocytoma of the optic nerve. Pa is histologically characterized by the presence of neoplastic bipolar astrocytes in compact areas a. Mapk signaling induces oncogeneinduced senescence ois, which may cause unpredictable growth behavior of pilocytic astrocytomas. Pilocytic astrocytoma, g it2braf, fusion, braf background pa is the most common glioma in the pediatric population 1 and it represents 5. They usually arise in the cerebellum, near the brainstem, in the hypothalamic region, or the optic chiasm, but they may occur in any area where astrocytes are present, including the cerebral hemispheres and the spinal cord.
Hence, it is commonly assumed that raf activation, either by fusion or by mutation, constitutes a critically important genetic event in pa tumorigenesis. Here, we identified 64 thalamic gliomas with clinical followup and characterized targeted genomic alterations. Pilocytic astrocytoma, the most common pediatric brain tumor, is a clinically. Recent progress in the pathology and genetics of pilocytic. Braf duplications and mapk pathway activation are frequent in. Dec 27, 2019 pediatric lowgrade gliomas plgg are the most frequent brain tumors in children. Mapk, neurofibromatosis, optic nerve, pilocytic astrocytoma. Pilocytic astrocytoma, as well as pleomorphic xanthoastrocytomas, frequently have braf alterations present in 70% of cases.
Pilocytic astrocytoma pa is the most common pediatric brain tumor. Shares common genetic alterations with pilocytic astrocytoma. Childhood astrocytomas treatment pdqhealth professional. Oct 23, 2017 pilocytic astrocytoma has a fiveyear survival rate of over 96 percent in children and young adults, which is one of the highest survival rates of any brain tumor. Duplication of 7q34 is specific to juvenile pilocytic. Heterogeneity of histopathological presentation of. Recent findings implicate aberrant activation of the mapk pathway, due to braf gene rearrangements or mutations, in 66%85% of sporadic pilocytic astrocytomas.
Abstract we report genetic aberrations that activate the erkmap kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high. Pi3kakt pathway alterations are associated with clinically. Practical molecular pathologic diagnosis of pilocytic. Importantly they, along with other pediatric lowgrade gliomas, lack idh mutations and tp53 mutations 6,7. Dec, 2011 pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. Braffgfr genomic alterations and activation of mapkerkmtor pathway. Nevertheless, up to 20% of patients may not be cured by surgery alone. Braf gene duplication constitutes a mechanism of mapk. Activation of the hedgehog pathway in pilocytic astrocytomas.
Genetic aberrations leading to mapk pathway activation mediate oncogeneinduced senescence in sporadic pilocytic astrocytomas karine jacob 1, donghanh quangkhuong, david t. Mar 31, 2020 44,45 taken together, the evidence of a brafkiaa1549 fusion in a glioma of uncertain or doubtful histology strongly points toward the diagnosis of a pilocytic astrocytoma, but it does not. Mar 20, 2015 the term pilocytic to describe astrocytoma variants has been used since the 1930s 8, 18 to indicate cells with hairlike, bipolar processes. The senescenceassociated secretory phenotype mediates. Most pas arise in the cerebellum, hypothalamus, and optic chiasm. The tumor tissue biopsy showed characteristic cells that look like fibers called rosenthal fibers. Mapk pathway activation in pilocytic astrocytoma ncbi nih. Europe pmc is an archive of life sciences journal literature.
Pilocytic astrocytoma pa is the most common primary brain tumor in children. The same pathway is also activated in plexiform neurofibromas pns which are lowgrade tumors involving peripheral nerves in patients with neurofibromatosis type 1 nf1. Symptoms of a jpa will vary depending upon the size and location of the tumor. Introduction pilocytic astrocytoma pa is a wellcircumscribed, welldifferentiated, slowly growing tumour, corresponding to who grade i. They share common genetic alterations braf duplication fusion, some pilomyxoid astrocytomas mature into classic pilocytic astrocytomas over time and intermediate forms exist. Several mechanisms lead to activation of this pathway in. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf. Pilocytic astrocytomas of the optic nerve and their relation to pilocytic. A novel git2braf fusion in pilocytic astrocytoma diagnostic. Kiaa1549braf fusion is the most common genetic event in pilocytic astrocytoma pa, and leads to activation of the mitogen activated protein kinase mapk signaling pathway.
From the department of pathology, johns hopkins hospital, baltimore. In fact, approximately 20 % of pediatric brain tumors are unclassifiable according to traditional schemes, most of which involve lowgrade gliomas burger pc, personal communication. Recent progress in the pathology and genetics of pilocytic and. Some arise in the cerebral hemispheres and other locations. Pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. Apr 27, 2017 pilocytic astrocytoma pa is the most common pediatric brain tumor. Pilocytic astrocytomas pas are the most common primary gliomas in children and adolescents. A new gtf2ibraf fusion mediating mapk pathway activation in. Pdf mapk pathway activation in pilocytic astrocytoma. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf kinase. Children affected by pilocytic astrocytoma can present with different symptoms that might include failure to thrive lack of appropriate weight gain weight loss, headache, nausea, vomiting, irritability, torticollis tilt neck or wry neck, difficulty to coordinate movements, and visual complaints including nystagmus. It is on the basis of histology that the diagnosis is rendered. In the united states, the annual incidence of pas is approximately 0.
Jones dt, gronych j, lichter p, witt o, pfister sm. An activating mutation of kras was identified in the single pilocytic astrocytoma without a braf or raf1 fusion. Jones5,8, hendrik witt5, sally lambert8, steffen albrecht2, olaf witt6, catherine vezina3, margret shirinian3, damien faury1,3, miklos garami 9, peter hauser, almos. Pediatric low grade gliomas plgg which include pilocytic astrocytoma pa are the most frequent brain tumors and represent 2530% of central nervous system tumors in children. Braf activation in pilocytic astrocytoma occurs most commonly through a brafkiaa1549 gene fusion, producing a fusion protein that lacks the braf regulatory domain. Our findings implicate aberrant activation of the mapk pathway due to gene duplication or mutation of braf as a molecular mechanism of pathogenesis in lowgrade astrocytomas and suggest inhibition of the mapk pathway as a potential treatment. Fgfr genes and dysregulated mapkerkmtor signaling in adult pilocytic astrocytoma. This who grade i neoplasm characteristically displays noninfiltrative growth and shows benign biological behavior that translates into a remarkably high 10year overall survival rate of greater than 90% upon gross total resection. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway activation in pilocytic astrocytoma. While some patients can be cured with surgery alone, more than 70% need complimentary treatments due to the location of tumors that preclude resection.
A recurrent feature of pa is deregulation of the mitogen activated protein kinase mapk pathway most often through kiaa1549braf fusion, but also by other braf or raf1gene fusions and point mutations e. Bipolar neoplastic cells with elongated hairlike processes that are arranged in parallel bundles and resemble mats of hair. Mapk pathway activation in pilocytic astrocytoma, so far reported in only a few cases, is fusion of a second raf kinase family member, raf1 or craf 61, 62, 81. However, their underlying moleculargenetic events are largely uncharacterized. Oncogenic raf1 rearrangement and a novel braf mutation as alternatives to kiaa1549. A new gtf2ibraf fusion mediating mapk pathway activation. Fgfr gene family alterations in lowgrade neuroepithelial. Here, we identified 64 thalamic gliomas with clinical followup and characterized targeted genomic alterations using. It confirms that optic nerve gliomas represent primarily pilocytic astrocytomas, and demonstrates mapk pathway activation in almost all cases, supporting targeting this pathway in patients with aggressive tumors. Histopathological analysis revealed a total of 21 neoplasias in the cerebral. Braffgfr genomic alterations and activation of mapk erkmtor pathway. A phase 2 study of trametinib for patients with pediatric.
Practical molecular pathologic diagnosis of pilocytic astrocytomas. Pilocytic astrocytoma, g it2braf, fusion, braf background pa is the most common glioma in the pediatric population 1 and it represents. Fusions of braf with other partner genes, as well as other genetic alterations not involving braf but also leading to mapk pathway activation have been described rarely. A body of research over recent years has demonstrated a key role for mitogenactivated protein kinase mapk pathway signaling in the development and behavior of pas. The indolent nature of this tumor allows for prolonged survival for most patients, rendering the disease a rather chronic one, with potential longterm sequelae that are occasionally related to treatment. Anaplastic pilocytic astrocytoma, abbreviated apa, is a rare highgrade astrocytoma.
Pilocytic astrocytoma pa is one of the most common brain cancers among children and activation of the mitogenactivated protein kinase mapk pathway is considered the hallmark. The second architectural pattern of pa is characterized by loose stroma, containing microcysts c and occasionally multinucleated cells. Rosenthal fibers are a frequent feature of pilocytic astrocytomas and may be numerous b. Braf fusion in activating the mapk pathway in pilocytic astrocytoma. Pilocytic astrocytoma has a fiveyear survival rate of over 96 percent in children and young adults, which is one of the highest survival rates of any brain tumor. Novel braf alteration in a sporadic pilocytic astrocytoma hindawi. After accounting for welldefined histopathologic categories, a subset of lowgrade gliomas remain diagnostic challenges, particularly in the pediatric population. Juvenile pilocytic astrocytoma jpa is a rare childhood brain tumor. Jul 14, 2009 recent reports have indicated a central role for the mitogenactivated protein kinase mapk pathway in the tumorigenesis of pilocytic astrocytomas and showed that duplication at 7q34 leads to a. Targeted detection of genetic alterations reveal the. The pilocytic astrocytoma is predominantly a tumor of childhood and the most common type of circumscribed astrocytoma. A followup tissue evaluation using immunohistochemistry showed alterations in mapk signaling pathway. We report genetic aberrations that activate the erkmap kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high frequency of gene fusions between kiaa1549 and braf among these tumours. Genomic alterations involving activation of braf and the erkmapk pathway are very common in sporadic cases of pilocytic astrocytoma, a type of lowgrade glioma.
Up to 50% will be refractory to conventional chemotherapy. Pilomyxoid astrocytoma is considered a variant of pilocytic astrocytoma. Gene expression profiles of nf1associated pilocytic. Gene expression profiles of nf1associated pilocytic astrocytomas and. Pubmed abstract korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Pfister s, janzarik wg, remke m, et al braf gene duplication constitutes a mechanism of mapk pathway activation in lowgrade astrocytomas. Abstract pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. It is included in the group of other astrocytic tumours in the revised 4th edition of the current 2016 who classification of tumours of. The most common histological entity in this setting is pilocytic astrocytoma pa, which accounts for approximately 20% of brain tumors under the. Recent reports have indicated a central role for the mitogenactivated protein kinase mapk pathway in the tumorigenesis of pilocytic astrocytomas. In one study, it was shown that the mapk pathway is activated in virtually all sporadic pilocytic astrocytomas 22.
It is now known that the majority of plgg have activation of the mapk erk pathway. Heterogeneity of histopathological presentation of pilocytic. Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. Oncogenic raf1 rearrangement and a novel braf mutation as. Pilocytic astrocytoma pa is the most frequently encountered glial tumor. Functional studies on gtf2ibraf showed elevated mapk pathway. Scheithauer, caterina giannini, amanda rynearson, ling cen, bridget hoesley, heather gilmerflynn, jann n sarkaria, sarah jenkins, jin long, fausto j. In the majority of cases, oncogenic braf fusions or braf v600e mutations are observed, while raf1 or nf1 alterations are more rarely found. Most common alteration is the braf duplication fusion resulting in activation of the mapk pathway. Pilocytic astrocytoma is a lowgrade glioma that affects mostly children and. Genetic aberrations leading to mapk pathway activation. Cns brain tumors 1 questions and study guide quizlet. Pi3kakt pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma erika f.
Despite distinctive histology and location of pns when compared to plgg, there is also an activation of the mapk. Sept 2012 mapk signaling as a therapeutic target in. Diagnostic role and relevance of braf status in brain tumors. Rgnts predominately affect young adults and are relatively rare neuroepithelial tumors with distinctive histologic features namely, the presence of neurocytes in rosettes or perivascular pseudorosettes in addition to an astrocytic component resembling pilocytic astrocytoma. Further fusions and activating mutations in braf were identified in 28% of grade ii astrocytomas, highlighting the importance of the erkmap kinase pathway in the development of paediatric lowgrade gliomas. Pilocytic astrocytomas pas are the most common primary gliomas in children and adolescents 019 years of age. It is included in the group of other astrocytic tumours in the revised 4th edition of the current 2016 who classification of tumours of the central nervous system 25. Fgfr genes and dysregulated mapkerkmtor signaling in adult pilocytic astrocytoma pankaj pathak department of pathology, all india institute of medical sciences, new delhi, india. The senescenceassociated secretory phenotype sasp has been shown to regulate ois, but its role in pilocytic astrocytoma.
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