In one study, it was shown that the mapk pathway is activated in virtually all sporadic pilocytic astrocytomas 22. Braf fusions, and leads to oncogene induced senescence ois. Genomic alterations involving activation of braf and the erkmapk pathway are very common in sporadic cases of pilocytic astrocytoma, a type of lowgrade glioma. Relative adc and location differ between posterior fossa. Braf activation in pilocytic astrocytoma occurs most commonly through a kiaa1549braf gene fusion, producing a fusion protein that lacks the braf regulatory domain. Brain tumours are the second largest group of childhood cancers comprising 2025% of cancer cases and are the leading cause of cancer. Pten and cdkn2a p16 deletions are frequent findings in diffusely infiltrating gliomas, particularly glioblastoma. Targeted detection of genetic alterations reveal the. Pilocytic astrocytoma pa is one of the most common brain cancers among children and activation of the mitogen activated protein kinase mapk pathway is considered the hallmark. Astrocytoma causes regional effects by compression, invasion, and destruction of brain parenchyma, arterial and venous hypoxia, competition for nutrients, release of metabolic end products e. Symptoms of a jpa will vary depending upon the size and location of the tumor. Heterogeneity of histopathological presentation of. This work was funded in part by the childrens cancer foundation and contributors to the pilocyticpilomyxoid astrocytoma fund, including laurens first and goal charles g eberhart, the childhood brain tumor foundation fausto j.
Ganglioglioma gg and pilocytic astrocytoma pa represent the most frequent lowgrade gliomas lgg occurring in paediatric age. Pilocytic astrocytoma pa is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. An activated mutant braf kinase domain is sufficient to. 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.
Activation of the map kinase mapk pathway caused by the brafv600e mutation or the kiaa1549braf fusion has been reported in. Oncogenic raf1 rearrangement and a novel braf mutation as alternatives to kiaa1549. Novel braf alteration in a sporadic pilocytic astrocytoma. Pediatric lowgrade gliomas plgg are the most frequent brain tumors in children. Shares common genetic alterations with pilocytic astrocytoma. Braf activation in pilocytic astrocytoma occurs most commonly through a brafkiaa1549 gene fusion, producing a fusion protein that lacks the braf regulatory domain. Gene expression profiles of nf1associated pilocytic. Pilocytic astrocytoma pa is the most frequently encountered glial tumor glioma or astrocytoma in children. Doctors said it was all gone, that was the end of it, no further treatment was necessary. Kras mutations are rare in jpas and have been found in 2% or less of cases. Pilocytic astrocytomas that occur in the optic pathway or hypothalamus have a slightly less favorable prognosis. Diencephalic syndrome nord national organization for. This mri shows a supratentorial glioblastoma multiforme.
Furthermore, activation of the rasmapk pathway in plga fails to explain the unique tendency of plga to growth arrest. Recent studies have identified alterations in the braf serinethreonine kinase gene as the likely causative mutation in these childhood brain tumors. Juvenile pilocytic astrocytoma jpa is a rare childhood brain tumor. The majority of these genetic changes involve chromosome 7q34 tandem duplication, resulting in aberrant braf fusion transcripts. This mri shows a pilocytic astrocytoma of the cerebellum. A glioma or astrocytoma is the most common tumor associated with diencephalic syndrome. Twentyfive years ago my son had a pilocytic astrocytoma completely removed from his left parietal lobe grade 1 benign. Pdf mapk pathway activation in pilocytic astrocytoma. Braf gene duplication constitutes a mechanism of mapk.
Because the concepts of oncogeneinduced senescence andor replicative senescence could explain the mechanism of ras activation leading to tumor growth arrest 20, 21, we hypothesized that in plga the bk. Genomic alterations involving braf activation are very common in sporadic cases of pilocytic astrocytoma, resulting in activation of the erkmapk pathway. Pilocytic astrocytomas pas are lowgrade gliomas that constitute approximately 20% of all pediatric central nervous system cns tumors. Braf gene duplication constitutes a mechanism of mapk pathway activation in lowgrade astrocytomas. Children with incompletely resected pa represent a clinically challenging patient. Mapk pathway activation through braf gene fusion in. In the majority of cases, oncogenic braf fusions or braf v600e mutations are observed, while raf1 or nf1 alterations are more rarely found. A complete cross section of the optic nerve is shown in the inset. Lggs not amenable of complete resection cr represent a challenging subgroup where traditional treatments often fail. Ligon, nci p01ca142536, and an unrestricted grant from. 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.
Genetic alterations resulting in constitutive activation of braf, a key tyrosine kinase in the mitogen activated protein kinase mapk pathway, are the defining abnormality in most pediatric lowgrade gliomas. Although myxoid change is prominent in specimen 1, the other feature of pilomyxoid astrocytoma, i. Braf duplications and mapk pathway activation are frequent. Pilomyxoid astrocytoma is considered a variant of pilocytic astrocytoma. This saturation of circumscribed and noninvasive lesions positive for mapk activation may partially explain the robust survival seen. Cin h, meyer c, herr r, janzarik wg, lambert s, jones dt, et al. Juvenile pilocytic astrocytomas jpas are relatively common low grade gliomas that are associated with mutations in genes that encode for proteins in the mapk pathway. Fusions of braf with other partner genes, as well as other genetic alterations not involving braf but also leading to mapk pathway activation have. Brafkiaa1549 fusion predicts better clinical outcome in. A phase 2 study of trametinib for patients with pediatric. Jones dt, hutter b, jager n, korshunov a, kool m, warnatz hj, et al. The diagnostic evaluation for astrocytoma includes magnetic resonance imaging mri of the brain or spine.
Importantly, it must be recognized that a limitation of this study in respect to mapk activation is the inclusion of pilocytic astrocytoma and ganglioglioma within the low grade histology category. An astrocytoma is a tumor that arises from the starshaped cells astrocytes that form the supportive tissue of the brain. Clinical and highresolution ct features of the covid19 infection. Most symptoms result from increased pressure on the brain and include headaches.
Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf kinase. 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. An activated mutant braf kinase domain is sufficient to induce pilocytic astrocytoma in mice. Recurrent somatic alterations of fgfr1 and ntrk2 in pilocytic astrocytoma. Pilocytic astrocytoma pa is the most common pediatric brain tumor, accounting for 20% of all brain tumors under the age of 20 1,2,3,4,5,6. They affect young children more than adolescents or adults and are important in the differential diagnosis of vision loss in children. Rodriguez, the dfci pediatric lowgrade astrocytoma foundation keith l. Jci an activated mutant braf kinase domain is sufficient. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway activation in pilocytic astrocytoma acta neuropathol, 121 2011, pp. Review mapk pathway activation in pilocytic astrocytoma david t. Clinical feasibility of gadoxetic acidenhanced isotropic highresolution 3dimensional magnetic resonance cholangiography using an iterative denoising algorithm for evaluation of the biliary anatomy of living liver donors november 27, 2019.
The single case lacking braf duplication or nf1association was more consistent with a ganglioglioma than a pilocytic astrocytoma, although it also had strong perk staining supporting mapk pathway activation. 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. Response of recurrent brafv600e mutated ganglioglioma to. Selumetinib in treating young patients with recurrent or. Activation of the hedgehog pathway in pilocytic astrocytomas. Recent findings implicate aberrant activation of the mapk pathway, due to braf gene rearrangements or mutations, in 66%85% of sporadic pilocytic astrocytomas. Comparison of the initial and followup changes march 17, 2020. Scheithauer, caterina giannini, amanda rynearson, ling cen, bridget hoesley, heather gilmerflynn, jann n. It is now known that the majority of plgg have activation of the mapkerk pathway. The tumor typically extends into the leptomeningeal space, expanding the dural sheath and compressing the remaining optic nerve proper, which is atrophic b. 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.
Pi3kakt pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma erika f. Jones jan gronych peter lichter olaf witt stefan m. They share common genetic alterations braf duplication fusion, some pilomyxoid astrocytomas mature into classic pilocytic astrocytomas over time and intermediate forms exist. 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. In most cases, the tumor is a benign, slow growing tumor that usually does not spread to surrounding brain tissue. Up to 50% will be refractory to conventional chemotherapy. Normally, astrocytes are responsible for a variety of roles, including providing nutrients to neurons, maintaining the bloodbrain barrier, and modulating neurotransmission how neurons communicate with each other. In the present study, we systematically investigated pediatric pilocytic and lowgrade diffuse astrocytomas for genomic imbalances by using highresolution arraycgh and identified frequent braf gene duplication as what we believe is a novel mechanism leading to mapk pathway activation in pediatric lowgrade astrocytomas. Braf fusion in activating the mapk pathway in pilocytic astrocytoma. 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 a benign brain tumor that arises from astrocytes, the supportive cells in the nervous system. An activated mutant braf kinase domain is sufficient to induce. The same pathway is also activated in plexiform neurofibromas pns which are lowgrade tumors involving peripheral nerves in patients with neurofibromatosis type.
It all started with a pilocytic astrocytoma mayo clinic. Bilateral fusiform enlargement of the optic nerve is virtually diagnostic of neurofibromatosis type 1 a. This section displays the typical biphasic pattern of a pilocytic astrocytoma, consisting of dense, relatively anuclear, fibrillar areas alternating with looser cystic fields. Even if surgery is successful, that child still has to have periodic mri scans to. Optic pathway gliomas opgs are lowgrade neoplasms intrinsic to the precortical visual pathway optic nerve, optic chiasm, tracts, and radiations. Several mechanisms lead to activation of this pathway in pa, mostly in a mutually exclusive manner, with constitutive braf. 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. Pilocytic astrocytoma pa is the most common tumor of the pediatric central nervous system cns. Activation of the mapk pathway is well established as the oncogenic driver of the disease. Oncogenic fam1bbraf fusion resulting from 7q34 deletion comprises an alternative mechanism of mapk pathway activation in pilocytic astrocytoma.