Optic pathway gliomas opgs are lowgrade neoplasms intrinsic to the precortical visual pathway optic nerve, optic chiasm, tracts, and radiations. Pilocytic astrocytomas of the optic nerve and their relation. Activation of the hedgehog pathway in pilocytic astrocytomas. They are one of the most common brain tumors seen in children, with approximately 700 children diagnosed with lowgrade astrocytoma a slowgrowing tumor each year. Pilocytic astrocytoma, the most common pediatric brain tumor, is a clinically. It is now known that the majority of plgg have activation of the mapkerk pathway.
In vitro analysis confirmed that kiaa1549braf induces constitutive kinase activity and is capable of transforming nih3t3 cells 6. 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. Some of the most common symptoms of a pediatric pilocytic astrocytoma include. Treatment of pns consists primarily of symptoms management andor surgical resection. The tumor tissue biopsy showed characteristic cells that look like fibers called rosenthal fibers. Pilocytic astrocytoma, the most common childhood brain tumor1, is typically associated with mitogenactivated protein kinase mapk. Heterogeneity of histopathological presentation of pilocytic. Braf gene duplication constitutes a mechanism of mapk pathway. However, in some cases, no apparent cancer driver events can be identified. Pilocytic astrocytoma pa is one of the most common brain cancers among children and activation of the mitogenactivated protein kinase mapk pathway is. The same pathway is also activated in plexiform neurofibromas pns which are lowgrade tumors involving peripheral nerves in patients with neurofibromatosis type 1 nf1.
Genomic alterations involving braf activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the erk mapk pathway. Importantly they, along with other pediatric lowgrade gliomas, lack idh mutations and tp53 mutations 6,7. It is now known that the majority of plgg have activation of the mapk erk pathway. 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. A juvenile pilocytic astrocytoma is the most common cause of diencephalic syndrome. Twentyfive years ago my son had a pilocytic astrocytoma completely removed from his left parietal lobe grade 1 benign. Juvenile pilocytic astrocytoma nord national organization. Lggs not amenable of complete resection cr represent a challenging subgroup where traditional treatments often fail. Genomic alterations involving activation of braf and the erkmapk pathway are very common in sporadic cases of pilocytic astrocytoma, a type of lowgrade glioma. These tumours arise preferentially in the cerebellum and the optic pathway, especially the hypothalamochiasmatic hc region.
The novel fusion was identified as part of a comprehensive genomic tumor. 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. However, it remains unknown whether mapk activation is present in the reactive gliosis of nonneoplastic lesions. The hedgehog hh pathway regulates the growth of higher who grade gliomas, and in this study, we have evaluated the activation and operational status of this regulatory pathway in pilocytic. Dec 19, 2014 ganglioglioma gg and pilocytic astrocytoma pa represent the most frequent lowgrade gliomas lgg occurring in paediatric age. Mapk pathway activation in pilocytic astrocytoma ncbi nih.
Aug 14, 2017 the difference in craffusionmediated activation of both mapk and pi3kmtor pathways in nih3t3 versus only mapk pathway in pmas could not be explained by differential expression level of fusion. The tumor may be in the form of a cyst and usually does not spread to nearby tissues. Recent findings implicate aberrant activation of the mapk pathway, due to braf gene rearrangements or mutations, in 66%85% of sporadic pilocytic astrocytomas. We need your help to find the best treatments for kids with cancer. Jones dt, gronych j, lichter p, witt o, pfister sm. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway activation in pilocytic astrocytoma. 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. As such, the symptoms of a pediatric pilocytic astrocytoma depend on the tumors size and where in the brain it is located. One of these cell lines was derived from a pediatric patient with a pilocytic astrocytoma who grade i, and 3 were established from adult patients with who grade ii tumors corresponding to diffuse astrocytoma 1 case or oligoastrocytoma 2. Dec 27, 2019 pediatric lowgrade gliomas plgg are the most frequent brain tumors in children.
The same pathway is also activated in plexiform neurofibromas pns which are lowgrade tumors involving peripheral nerves in patients with neurofibromatosis type. Nevertheless, the biologic significance of braf oncogene activation lies in its ability to activate the mitogenactivated protein kinase pathway, a wellrecognized early alteration in astrocytomas, 40 as well as other cutaneous and gastric neoplasms, such as melanocytic nevi and colorectal serrated polyps. Practical molecular pathologic diagnosis of pilocytic astrocytomas. Ganglioglioma gg and pilocytic astrocytoma pa represent the most frequent lowgrade gliomas lgg occurring in paediatric age. Downstream activation of the mapk pathway was confirmed by high levels of phosphorylated mek and erk mapk in the presence of the braf fusion products 8. Today, what we call pilocytic astrocytoma pa has had a number of names before the who classification system became generally accepted. Practical molecular pathologic diagnosis of pilocytic. Symptoms of a jpa will vary depending upon the size and location of the tumor. Mapk pathway activation in pilocytic astrocytoma david t. Gene expression profiles of nf1associated pilocytic. The patients had either near complete resolution of the primary tumor braf p.
This is because total removal resection of the tumor is often curative. Pilocytic astrocytomas pa are who grade i brain tumours that occur predominantly in childhood and display benign behaviour louis et al. Pilocytic astrocytoma, as well as pleomorphic xanthoastrocytomas, frequently have braf alterations present in 70% of cases. Genomic testing of disseminated pilocytic astrocytomas, particularly. Heterogeneity of histopathological presentation of. It all started with a pilocytic astrocytoma mayo clinic.
Activation of the map kinase mapk pathway caused by the brafv600e mutation or the kiaa1549braf fusion has been reported in. Targeted mapk pathway inhibitors in patients with disseminated. Pfister s, janzarik wg, remke m, et al braf gene duplication constitutes a mechanism of mapk pathway activation in lowgrade astrocytomas. Response of recurrent brafv600e mutated ganglioglioma to.
Jones dt, hutter b, jager n, korshunov a, kool m, warnatz hj, et al. Pilocytic astrocytomas of the optic nerve and their. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf kinase. Pilocytic astrocytoma prognosis, survival rate and. Up to 50% will be refractory to conventional chemotherapy. 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. An overactive signaling pathway is a common cause in cases of pilocytic astrocytoma, the most frequent type of brain cancer in children. Pediatric lowgrade gliomas plgg are the most frequent brain tumors in children. Braf fusion in activating the mapk pathway in pilocytic astrocytoma. Surgery is the treatment of choice for this type of tumor. Mapk pathway activation in pilocytic astrocytoma springerlink. Pilocytic astrocytoma is an often benign, slowgrowing tumor of the brain or spinal cord. A phase 2 study of trametinib for patients with pediatric.
Read her explanation of astrocytoma symptoms, treatment options, and research opportunities. Genomic alterations involving braf activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the erkmapk pathway. Oct 23, 2017 pilocytic astrocytoma is a rare type of brain tumor that occurs mostly in children and young adults under age 20. A novel git2braf fusion in pilocytic astrocytoma diagnostic.
Recurrent somatic alterations of fgfr1 and ntrk2 in pilocytic. 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%. What other diseasecondition shares some of these symptoms. Learn vocabulary, terms, and more with flashcards, games, and other study tools. This results in overexpression of braf at the mrna and protein levels and consecutive activation of downstream signaling components. Childhood astrocytomas treatment pdq health professionals. 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 the most common pediatric brain tumor. Craf gene fusions in pediatric lowgrade gliomas define a. 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. As a pilocytic astrocytoma grows, it presses on surrounding healthy parts of the brain, affecting their function. An activating mutation of kras was identified in the single pilocytic astrocytoma without a braf or raf1 fusion. Pdf mapk pathway activation in pilocytic astrocytoma. Pilocytic astrocytoma is a lowgrade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system.
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. Left excessive mapk activation can induce irreversible cell cycle arrest via the p16 ink4a rb or the p14 arf p53 pathway. 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. Braf activation in pilocytic astrocytoma occurs most commonly through a kiaa1549braf gene fusion, producing a fusion protein that lacks the braf regulatory domain. Raf1 fusion activating the mapk pathway in pilocytic astrocytoma christina westmose yde a, astrid sehested b, angels mateuregue a, olga ostrup a, david scheie c, karsten nysom b, finn cilius nielsen a. In the majority of cases, oncogenic braf fusions or braf v600e mutations are observed, while raf1 or nf1 alterations are more rarely found. For more information, choose juvenile pilocytic astrocytoma as your search term in the rare disease database. Cns brain tumors 1 questions and study guide quizlet. Braf gene duplication constitutes a mechanism of mapk pathway activation in lowgrade astrocytomas.
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. A new gtf2ibraf fusion mediating mapk pathway activation in. In most cases, the tumor is a benign, slow growing tumor that usually does not spread to surrounding brain tissue. Genetic alterations within the mapk signaling pathway are a hallmark of this tumor. Mapk pathway activation in pilocytic astrocytoma mapk pathway activation in pilocytic astrocytoma. A followup tissue evaluation using immunohistochemistry showed alterations in mapk signaling pathway.
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. Most symptoms result from increased pressure on the brain and include headaches, nausea, vomiting, balance problems, and vision abnormalities. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf. Braf activation in pilocytic astrocytoma occurs most commonly through a brafkiaa1549 gene fusion, producing a fusion protein that lacks the braf regulatory domain. Baldricks scholar, about astrocytoma, a type of childhood cancer. Recurrent somatic alterations of fgfr1 and ntrk2 in pilocytic astrocytoma. A recurrent feature of pa is deregulation of the mitogen activated protein. Braf gene duplication constitutes a mechanism of mapk. Novel braf alteration in a sporadic pilocytic astrocytoma hindawi. In one study, it was shown that the mapk pathway is activated in virtually all sporadic pilocytic astrocytomas 22. Korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Juvenile pilocytic astrocytoma jpa is a rare childhood brain tumor.
Pilocytic astrocytoma in children danafarberboston. 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. Diencephalic syndrome nord national organization for. Activation of the map kinase mapk pathway caused by the brafv600e mutation or the kiaa1549braf fusion has been reported in pediatric gg and pa. Dec, 2011 pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. 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. Pubmed abstract korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma.
Davies h, bignell gr, cox c, stephens p, edkins s, clegg s. This was discovered by a network of scientists coordinated by the german cancer research center as part of the international cancer genome consortium, icgc. The difference in craffusionmediated activation of both mapk and pi3kmtor pathways in nih3t3 versus only mapk pathway in pmas could not be explained by differential expression level of fusion. In all 96 cases studied, the researchers found defects in genes involved in a particular pathway. Gene expression profiles of nf1associated pilocytic astrocytomas and. Doctors said it was all gone, that was the end of it, no further treatment was necessary. Activation of mtorc1mtorc2 signaling in pediatric lowgrade glioma and. Raf1 fusion activating the mapk pathway in pilocytic. Astrocytoma is a type of tumor that can happen in the brain or spinal cord. They affect young children more than adolescents or adults and are important in the differential diagnosis of vision loss in children.
Frequent gains at chromosome 7q34 involving braf in pilocytic astrocytoma. Diencephalic syndrome nord national organization for rare. Symptoms vary depending upon the size and location of the tumor. Pilocytic astrocytoma pa, featuring activation of the mitogenactivated protein kinase mapk pathway, is the most common tumor of the pediatric central nervous system.
Mapk pathway activation through braf gene fusion in. 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. Childhood astrocytomas treatment pdqhealth professional. It is included in the group of other astrocytic tumours in the revised 4th edition of the current 2016 who classification of tumours of. Pilocytic astrocytoma pa is the most frequently encountered glial tumor. Pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. Mitogenactivated protein kinase in gliosis and pilocytic. Oncogeneinduced senescence in pilocytic astrocytoma. 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. The term pilocytic to describe astrocytoma variants has been used since the 1930s 8, 18 to indicate cells with hairlike, bipolar processes. Pilocytic astrocytoma is a rare type of brain tumor that occurs mostly in children and young adults under age 20. If the pilocytic astrocytoma is causing symptoms or a scan shows that the tumor is growing, a doctor may advise treatment. Introduction pilocytic astrocytoma pa is a wellcircumscribed, welldifferentiated, slowly growing tumour, corresponding to who grade i.
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