Mapk pathway activation through braf gene fusion in. Childhood astrocytomas treatment pdqhealth professional. Pilocytic astrocytomas of the optic nerve and their relation to pilocytic. To conclude, this is the first study demonstrating the occurrence of the kiaa1549braf fusion with activation of the mapk erk pathway in podgs. Pilocytic astrocytomas pas are the most common primary gliomas in children and adolescents 019 years of age.
Pubmed abstract korshunov a, meyer j, capper d, et al combined molecular analysis of braf and idh1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. 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%. They share common genetic alterations braf duplication fusion, some pilomyxoid astrocytomas mature into classic pilocytic astrocytomas over time and intermediate forms exist. Recent progress in the pathology and genetics of pilocytic. Department of pathology, laboratory for molecular pathology, copenhagen. Focused pilocytic astrocytoma with stained slides of. Oncogenic raf1 rearrangement and a novel braf mutation as alternatives to kiaa1549. Recently, a new mechanism for activation of braf was identified resulting from a tandem duplication, generating a fusion protein with constitutive braf activity and thereby activating the mapk pathway. The term pilocytic to describe astrocytoma variants has been used since the 1930s 8, 18 to indicate cells with hairlike, bipolar processes.
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. Mapk pathway activation through braf gene fusion in pilocytic. Genomic analysis in the practice of surgical neuropathology. This paper reports on a case of pilocytic astrocytoma pa, for which a. 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. Pilocytic astrocytoma, g it2braf, fusion, braf background pa is the most common glioma in the pediatric population 1 and it represents 5. Under nonpathological conditions, mapkerk signaling.
The nf1 protein, called neurofibromin, acts in the mitogenactivated protein map kinase pathway as a gtpaseactivating protein for ras. Abstract we report genetic aberrations that activate the erkmap kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high. Gene expression profiles of nf1associated pilocytic. In one study, it was shown that the mapk pathway is activated in virtually all sporadic pilocytic astrocytomas 22. Mapk pathway activation in pilocytic astrocytoma of the optic nerve. The pilocytic astrocytoma is predominantly a tumor of childhood and the most common type of circumscribed astrocytoma. 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. Importantly they, along with other pediatric lowgrade gliomas, lack idh mutations and tp53 mutations 6,7.
So mutations or duplications of the braf gene will lead to oncogenic activation fig. Heterogeneity of histopathological presentation of pilocytic. Pfister s, janzarik wg, remke m, et al braf gene duplication constitutes a mechanism of mapk pathway activation in lowgrade astrocytomas. 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. A phase 2 study of trametinib for patients with pediatric. Mapk pathway activation in pilocytic astrocytoma springerlink. 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. Activation of the hedgehog pathway in pilocytic astrocytomas. Mapk signaling in normal brain and highgrade astrocytomas. Pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. Recent studies have identified alterations in the braf serinethreonine kinase gene as the likely causative mutation in these childhood brain tumors. Pediatric lowgrade gliomas plgg are frequently driven by genetic alterations in the ras mitogenactivated protein kinase ras mapk pathway yet sho. Therefore this study provides a rationale for potential therapeutic advantage of targeting mapkerk and mtor pathway in adult pas. Oncogeneinduced senescence ois was first reported when the.
Clinical significance of molecular diagnosis of pilocytic astrocytoma. Braf fusion in activating the mapk pathway in pilocytic astrocytoma. Braf duplications and mapk pathway activation are frequent in. Mapk pathway activation in pilocytic astrocytoma mapk pathway activation in pilocytic astrocytoma. Pilocytic astrocytoma pa is the most common pediatric brain tumor. Pathological diagnosis was an anaplastic astrocytoma aa, not otherwise.
The activation of constitutive braffgfr related mapk erk signaling along with mtor appears to be an important oncogenic event in adult pas and may be constituting to the aggressive tumor behavior of adults. Diffuse astrocytomas are common glial tumours and grouped together with oligodendroglioma in the current who brain tumor classficiation. Diagnostic role and relevance of braf status in brain tumors. 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. Pilocytic astrocytoma is a lowgrade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Bipolar neoplastic cells with elongated hairlike processes that are arranged in parallel bundles and resemble mats of hair.
A novel git2braf fusion in pilocytic astrocytoma diagnostic. Under nonpathological conditions, mapkerk signaling components are. Dec, 2011 pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. 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 ras mapk signaling pathway plays a significant role in cell growth, differentiation, and apoptosis. A recent cbtrus report stated that pas account for approximately 15. Genomic alterations involving braf activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the erk mapk pathway.
Senescence is a physiologic phenomenon characterized by a permanent cellcycle arrest. Introduction pilocytic astrocytoma pa is a wellcircumscribed, welldifferentiated, slowly growing tumour, corresponding to who grade i. Histology was remarkable for a lowgrade glioma composed of mildly atypical. Oncogenic raf1 rearrangement and a novel braf mutation as. Europe pmc is an archive of life sciences journal literature. An astrocytoma is a neoplasm derived from an astrocyte. Pilocytic astrocytomas pas are lowgrade gliomas that constitute approximately 20% of all pediatric central nervous system cns tumors. Mapk pathway activation in pilocytic astrocytoma david t. T1 braf duplications and mapk pathway activation are frequent in gliomas of the optic nerve proper. 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. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway activation in pilocytic astrocytoma.
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. Integrated molecular and clinical analysis of 1,000. Novel braf alteration in a sporadic pilocytic astrocytoma hindawi. Braf activation in pilocytic astrocytoma occurs most commonly through a kiaa1549braf gene fusion, producing a fusion protein that lacks the braf regulatory domain. Pilomyxoid astrocytoma is considered a variant of pilocytic astrocytoma. Today, what we call pilocytic astrocytoma pa has had a number of names before the who classification system became generally accepted. 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. Mapk pathway activation through braf gene fusion in pilocytic astrocytomas. Braf gene duplication constitutes a mechanism of mapk pathway. Mar 31, 2020 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. Oncogenic kiaa1549braf fusion with activation of the mapk.
Novel braf alteration in a sporadic pilocytic astrocytoma. Genetic aberrations leading to mapk pathway activation. Jones dt, hutter b, jager n, korshunov a, kool m, warnatz hj, et al. 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. Recurrent somatic alterations of fgfr1 and ntrk2 in pilocytic astrocytoma. Braffgfr genomic alterations and activation of mapkerkmtor pathway. 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. Pilocytic astrocytoma pa is the most frequently encountered glial tumor glioma or astrocytoma in children. Different fusion variants involving braf and kiaa1549 were demonstrated, present in 80% of pilocytic astrocytomas in children. Braffgfr genomic alterations and activation of mapk erkmtor pathway. Health, general genetic aspects extracellular signalregulated kinases research gliomas oncogenes tumors. Pilocytic astrocytoma, as well as pleomorphic xanthoastrocytomas, frequently have braf alterations present in 70% of cases. Some often circumscribed astrocytic tumors are biologically different from diffuse astrocytomas an overview of cns tumours is found in the cns tumours.
Practical molecular pathologic diagnosis of pilocytic. 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. 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 mapkerk pathway activation in hereditary pas. Pdf mapk pathway activation in pilocytic astrocytoma. Braf is a protooncogene that works as a downstream target for the ras protein. Pilocytic astrocytoma is the most common pediatric brain tumor and commonly viewed as a benign lesion with excellent prognosis. 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. Braf gene duplication constitutes a mechanism of mapk. Webpathology is a free educational resource with 10274 high quality pathology images of benign and malignant. Mapk pathway activation in pilocytic astrocytoma ncbi nih. To determine the distinction of pilocytic astrocytoma of the optic nerve from. Judith wm jeuken and pieter wesseling, corrigendum.
Recent progress in the pathology and genetics of pilocytic and pilomyxoid astrocytomas. To conclude, this is the first study demonstrating the occurrence of the kiaa1549braf fusion with activation of the mapkerk pathway in podgs. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf. It is included in the group of other astrocytic tumours in the revised 4th edition of the current 2016 who classification of tumours of.
Brain tumours are the second largest group of childhood cancers comprising 2025% of cancer cases and are the leading cause of cancer. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf kinase. A new gtf2ibraf fusion mediating mapk pathway activation in. 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. Pilocytic astrocytoma, g it2braf, fusion, braf background pa is the most common glioma in the pediatric population 1 and it represents. Pas demonstrate mapk signaling pathway activation through. These fusions were identified from analysis of focal copy number gains at 7q34, detected using affymetrix 250k and 6.
Pilocytic astrocytoma pa is the most frequently encountered glial tumor. The presence of the kiaa1549braf fusion in podg may not be uncommon, as adult odgs have also been reported to harbor this alteration in 16% of cases 6. Fusionindependent rsk1 over expression in pilocytic astrocytoma. Activation of the p4442 mitogen activated protein kinase mapk has been implicated in several neoplasias5 14 and is thought to be important in the pathogenesis of pas in children. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas pa, the most prevalent brain neoplasm in children. The activation of constitutive braffgfr related mapkerk signaling along with mtor appears to be an important oncogenic event in adult pas and may be constituting to the aggressive tumor behavior of adults. All of these observations converge to indicate a major role of mapk pathway activation in the clinical course and biology of pa.
Braf activation in pilocytic astrocytoma occurs most commonly through a brafkiaa1549 gene fusion, producing a fusion protein that lacks the braf regulatory domain. In the united states, the annual incidence of pas is approximately 0. Therefore this study provides a rationale for potential therapeutic advantage of targeting mapk erk and mtor pathway in adult pas. Genomic alterations involving braf activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the erkmapk pathway. Genomic alterations involving activation of braf and the erkmapk pathway are very common in sporadic cases of pilocytic astrocytoma, a type of lowgrade glioma. 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.
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