Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. Apr 27, 2017 pilocytic astrocytoma pa is the most common pediatric brain tumor. May 01, 2008 in summary, we identified a mechanism of mapk pathway activation in lowgrade astrocytomas via duplication of the braf gene locus. Recent progress in the pathology and genetics of pilocytic.
Dec, 2011 pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. 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, g it2braf, fusion, braf background pa is the most common glioma in the pediatric population 1 and it represents 5. Diencephalic syndrome nord national organization for. 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. However, the clinical significance of this genetic alteration is. Pilocytic astrocytoma is a lowgrade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. A juvenile pilocytic astrocytoma is the most common cause of diencephalic syndrome. Pilocytic astrocytoma prognosis, survival rate and. Oncogenic raf1 rearrangement and a novel braf mutation as.
The term pilocytic to describe astrocytoma variants has been used since the 1930s 8, 18 to indicate cells with hairlike, bipolar processes. Here, we identified 64 thalamic gliomas with clinical followup and characterized targeted genomic alterations using. Pilocytic astrocytoma pa is the most common pediatric brain tumor. For more information, choose juvenile pilocytic astrocytoma as your search term in the rare disease database. 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. Therapeutic targets in pilocytic astrocytoma based on genetic analysis. 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. Childhood astrocytomas treatment pdq health professionals. 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. Surgical resection is the treatment of choice for pilocytic astrocytoma in children, and. Pubmed abstract korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma.
Activation of the hedgehog pathway in pilocytic astrocytomas. This results in overexpression of braf at the mrna and protein levels and consecutive activation of downstream signaling components. Understanding paediatric gliomas at the molecular level provides important prognostic and therapeutic insights, such as which genetic alterations confer a favourable response to adjuvant. Ras signaling regulates an array of cellular functions such as cell growth, survival, and differentiation through the activation of downstream signaling pathways, the. Pilocytic astrocytoma pa was initially described as spongioblastoma by bailey and cushing 1 in 1926 as a group of tumors that occur in the cerebellar region in children and show a longterm postoperative survival. Molecular analysis of pediatric brain tumors identifies micrornas in. Pa has an extremely favorable prognosis, generally following a protracted, indolent course after surgical resection. Molecular diagnostics in paediatric glial tumours the.
Therapeutic targets in pilocytic astrocytoma based on genetic. They affect young children more than adolescents or adults and are important in the differential diagnosis of vision loss in children. Braf gene duplication constitutes a mechanism of mapk. A pilocytic astrocytoma is a brain tumor that originates from starshaped cells called astrocytes. Alt and atrx loss, as well as alterations involving the mapk pathway, are. 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. Pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. Our findings implicate aberrant activation of the mapk pathway due to. 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. Mapk pathway activation through braf gene fusion in pilocytic astrocytomas. In one study, it was shown that the mapk pathway is activated in virtually all sporadic pilocytic astrocytomas. Some have a favorable prognosis, especially if completely resected better prognosis than diffuse astrocytomas.
Diencephalic syndrome nord national organization for rare. Scheithauer, caterina giannini, amanda rynearson, ling cen, bridget hoesley, heather gilmerflynn, jann n sarkaria, sarah jenkins, jin long, fausto j. In the near future, interference with the fusion gene causing activation of the mapk signalling cascade may open new therapeutic avenues for children with pilocytic astrocytomas, as a first line of defence against tumour growth or in situations where the tumour has become refractory to other therapeutic modalities. An overview of the most common rasmapk pathway alterations in plgg is shown in fig. 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. 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. Optic pathway gliomas opgs are lowgrade neoplasms intrinsic to the precortical visual pathway optic nerve, optic chiasm, tracts, and radiations. Oncogenic brafras or nf1 loss can potentially trigger oncogeneinduced senescence ois through activation of the mitogenactivated protein kinase mapk pathway. Furthermore, activation of the ras mapk pathway in plga fails to explain the unique tendency of plga to growth arrest. Mapk pathway activation in pilocytic astrocytoma of the optic nerve.
Diagnostic role and relevance of braf status in brain tumors. Recent findings implicate aberrant activation of the mapk pathway, due to braf gene rearrangements or mutations, in 66%85% of sporadic pilocytic astrocytomas. Mitogenactivated protein kinase in gliosis and pilocytic. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas pa, the most prevalent brain neoplasm in children. Jones5,8, hendrik witt5, sally lambert8, steffen albrecht2, olaf witt6, catherine vezina3, margret shirinian3, damien faury1,3, miklos garami 9, peter hauser, almos. The mapk pathway constitutes a potential drug target in lowgrade astrocytomas.
The diagnostic and prognostic potential of kiaa1549braf fusion in. Astrocytes are a kind of glial cell, cells that support and nourish neurons in the brain. Pilocytic astrocytomas pas are lowgrade gliomas that constitute approximately 20% of all pediatric central nervous system cns tumors. Pediatric lowgrade glioma in the era of molecular diagnostics acta. Activation of the map kinase mapk pathway caused by the brafv600e mutation or the kiaa1549braf fusion has been reported in pediatric gg and pa.
Gene expression profiles of nf1associated pilocytic astrocytomas and sporadic pilocytic astrocytomas showed similar activation of mapk pathway target genes, further indicating that the mapk pathway is commonly involved in the pathogenesis of sporadic astrocytomas as well 24, 25. Introduction pilocytic astrocytoma pa is a wellcircumscribed, welldifferentiated, slowly growing tumour, corresponding to who grade i. Pfister s, janzarik wg, remke m, et al braf gene duplication constitutes a mechanism of mapk pathway activation in lowgrade astrocytomas. Pilocytic astrocytoma, as well as pleomorphic xanthoastrocytomas, frequently have braf alterations present in 70% of cases. Genetic aberrations leading to mapk pathway activation mediate oncogeneinduced senescence in sporadic pilocytic astrocytomas karine jacob 1, donghanh quangkhuong, david t. The constitutive activation of the mapk pathway increases survival and.
Pilocytic astrocytoma pa is the most frequent pediatric brain tumor its most common location is the cerebellum and it develops during the first two decades of life. Heterogeneity of histopathological presentation of. Pilocytic astrocytoma is the most common pediatric brain tumor and commonly viewed as a benign lesion with excellent prognosis. Subependymal giant cell astrocytoma represents another lowgrade, predominantly pediatric, astrocytoma that almost always occurs in the setting of tuberous sclerosis complex, which can serve as a model for this type of targeted therapy given the recent clinical success of mtor inhibitors. Genomic alterations involving activation of braf and the erk mapk pathway are very common in sporadic cases of pilocytic astrocytoma, a type of lowgrade glioma. Pilocytic astrocytomas pas are the most common primary gliomas in children and adolescents. Introduction pilocytic astrocytomas of who grade i are the most common pri. Recent progress in the pathology and genetics of pilocytic and. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf kinase. Pilocytic astrocytomas, the most common glioma subtype in children and young adults, represent, among brain tumors, the neoplasms that more frequently show constitutive activation of the mapk.
Brafkiaa1549 fusion predicts better clinical outcome in pediatric lowgrade astrocytoma cynthia hawkins1,4. Mapk pathway activation in pilocytic astrocytoma springerlink. 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. Aug 31, 2016 paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. Activation of mtorc1mtorc2 signaling in pediatric low. Heterogeneity of histopathological presentation of pilocytic.
Astrocytomas that occur in association with diencephalic syndrome tend to be more aggressive and to develop at an earlier age than other astrocytomas arising in the same area. The usual firstline treatment of pilocytic and diffuse astrocytomas. Mapk pathway activation through braf gene fusion in pilocytic. Childhood astrocytomas treatment pdqhealth professional. Targeted detection of genetic alterations reveal the.
Pilocytic astrocytomas of the optic nerve and their relation. A new gtf2ibraf fusion mediating mapk pathway activation. Molecular analysis of pediatric brain tumors identifies. Pdf mapk pathway activation in pilocytic astrocytoma. Dec 19, 2014 ganglioglioma gg and pilocytic astrocytoma pa represent the most frequent lowgrade gliomas lgg occurring in paediatric age. The increased incidence of pas in patients with neurofibromatosis type 1 and the identification of inactivation of both nf1 genes in these tumours resulting in hyperactive ras signalling and subsequent raf activation imply a role of mapk erk pathway activation in hereditary pas as well, albeit via another mechanism. Pi3kakt pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma erika f. In the majority of cases, oncogenic braf fusions or braf v600e mutations are observed, while raf1 or nf1 alterations are more rarely found. Pilocytic astrocytoma is a lowgrade glioma that affects mostly children and. Most common alteration is the braf duplication fusion resulting in activation of the mapk pathway. Raf1 fusion activating the mapk pathway in pilocytic. Braf fused tumors, the activated raf1 domain results in activation of the map kinase pathway 7.
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. An activating mutation of kras was identified in the single pilocytic astrocytoma without a braf or raf1 fusion. Lggs not amenable of complete resection cr represent a challenging subgroup where traditional treatments often fail. Mapk pathway activation through braf gene fusion in. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Pilocytic astrocytoma, g it2braf, fusion, braf background pa is the most common glioma in the pediatric population 1 and it represents.
Although a substantial amount of data has been collected in a very short period of time, the clinicobiological implication of the bk fusion in plga is still unclear. In these cases, misdiagnosis may result in overtreatment, leading to. Targeting the rasrafmekerk signaling pathway in gliomas. In the near future, interference with the fusion gene. A novel git2braf fusion in pilocytic astrocytoma diagnostic. Importantly they, along with other pediatric lowgrade gliomas, lack idh mutations and tp53 mutations 6,7.
Pilocytic astrocytomas are slowgrowing tumors that usually occur in the. Pas generally have an excellent prognosis and are classi fied as who. However, it remains unknown whether mapk activation is present in the reactive gliosis of nonneoplastic lesions. Further more, the loss of p16 has been reported in some anaplastic pa 42,71, and a recent study involving 73 anaplastic astrocytomas with pilocytic features found that these gliomas are characterized by frequent mapk pathway alterations, cdkn2ab deletion, atrx loss, and unfavorable prognosis. Pilocytic astrocytoma pa, featuring activation of the mitogenactivated protein kinase mapk pathway, is the most common tumor of the pediatric central nervous system. Mar 11, 2010 pilocytic astrocytoma is the most common pediatric brain tumor and commonly viewed as a benign lesion with excellent prognosis. Pilomyxoid astrocytoma is considered a variant of pilocytic. A body of research over recent years has demonstrated a key role for mitogenactivated protein. Genomic alterations involving braf activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the erkmapk pathway. Health organisation, and prognosis in terms of overall. Pilocytic astrocytomas, the most common glioma subtype in children and young adults, represent, among brain tumors, the neoplasms that more frequently show constitutive activation of. Cancers free fulltext oncogenic braf alterations and their.
May 24, 20 pilocytic astrocytoma is a lowgrade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. 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. Pilocytic astrocytoma pa is one of the most common brain cancers among children and activation of the mitogenactivated protein kinase mapk pathway is.
Pilocytic astrocytoma in children danafarberboston. In summary, we identified a mechanism of mapk pathway activation in lowgrade astrocytomas via duplication of the braf gene locus. Glial tumours in children have distinct patterns of epigenetic alteration, chromosomal structure, and gene and protein expression that differentiate them from their histological counterparts in adults. Genetic aberrations leading to mapk pathway activation. A new gtf2ibraf fusion mediating mapk pathway activation in. Activation of the map kinase mapk pathway caused by the brafv600e mutation or the kiaa1549braf fusion has been reported in. Genomic alterations involving activation of braf and the erkmapk pathway are very common in sporadic cases of pilocytic astrocytoma, a type of lowgrade glioma. Here, we identified 64 thalamic gliomas with clinical followup and characterized targeted genomic alterations. To provide first preclinical evidence for a potential role of specific pharmacological inhibitors of the mapk pathway in the tailored treatment of lowgrade astrocytomas, we made use of 4 cell lines established from primary lowgrade gliomas. Shares common genetic alterations with pilocytic astrocytoma.
It is included in the group of other astrocytic tumours in the revised 4th edition of the current 2016 who classification of tumours of. Response of recurrent brafv600e mutated ganglioglioma to. Because of the longterm survival of the vast majority of patients, pilocytic astrocytoma. Ganglioglioma gg and pilocytic astrocytoma pa represent the most frequent lowgrade gliomas lgg occurring in paediatric age. Brafkiaa1549 fusion predicts better clinical outcome in. Braf activation in pilocytic astrocytoma occurs most commonly through a brafkiaa1549 gene fusion, producing a fusion protein that lacks the braf regulatory domain. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf. Braf fusion in activating the mapk pathway in pilocytic astrocytoma. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway activation in pilocytic astrocytoma. Braf activation in pilocytic astrocytoma occurs most commonly through a kiaa1549braf gene fusion, producing a fusion protein that lacks the braf regulatory domain. Today, what we call pilocytic astrocytoma pa has had a number of names before the who classification system became generally accepted. Oct 23, 2017 pilocytic astrocytoma is a rare type of brain tumor that occurs mostly in children and young adults under age 20. Oncogenic raf1 rearrangement and a novel braf mutation as alternatives to kiaa1549. Pilocytic astrocytomas of the optic nerve and their relation to pilocytic.
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