PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma

Pilocytic astrocytomas (PA) are well-differentiated gliomas having a favorable prognosis when compared with other diffuse or infiltrative astrocytomas. Molecular genetic abnormalities and activation of signaling pathways associated with clinically aggressive PA and histologically anaplastic PA have not been adequately studied. We performed molecular genetic, gene expression, and immunohistochemical studies using three PA subsets, including conventional PA (n?=?43), clinically aggressive/recurrent PA (n?=?24), and histologically anaplastic PA (n?=?25). A clinical diagnosis of NF1 was present in 28% of anaplastic PA. Molecular cytogenetic studies demonstrated heterozygous PTEN/10q and homozygous p16 deletions in 6/19 (32%) and 3/15 (20%) cases of anaplastic PA, respectively, but in neither of the two other groups. BRAF duplication was identified in 33% of sporadic anaplastic PA and 63% of cerebellar examples. BRAF (V600E) mutation was absent in four (of 4) sporadic cases lacking duplication. IDH1(R132H) immunohistochemistry was negative in 16 (of 16) cases. Neither PDGFRA nor EGFR amplifications were present. pERK staining levels were similar among the three PA subsets, but a stepwise increase in cytoplasmic pAKT and to a lesser extent pS6 immunoreactivity was noted by immunohistochemistry in aggressive PA groups. This was particularly true in histologically anaplastic PA when compared with conventional PA (p?相似文献   

Update on molecular findings, management and outcome in low-grade gliomas

Low-grade infiltrating gliomas in adults include diffuse astrocytoma, oligoastrocytoma and oligodendroglioma. The current gold standard diagnosis of these tumors relies on histological classification; however, emerging molecular abnormalities discovered in these tumors are playing an increasingly prominent part in the process of tumor diagnosis and, consequently, patient management. The frequency and clinical importance of tumor protein p53 (TP53) abnormalities, deletions involving chromosomes 1p and 19q, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, abnormalities in the PTEN tumor suppressor gene and the BRAF oncogene, and isocitrate dehydrogenase (IDH) mutations have become better defined. Molecular markers have not, historically, had an important role in determining the course of treatment for patients with low-grade gliomas, but ongoing phase III clinical trials incorporate 1p deletion or 1p19q codeletion status-and future trials plan to incorporate MGMT promoter methylation status-as stratification factors. Future trials will need to incorporate IDH mutational status in addition to these factors. Ultimately, molecular marker assessment will, hopefully, improve the accuracy of tumor diagnosis and enhance the effectiveness of treatment to achieve improved patient outcomes.     

Neurofibromatosis 1

Neurofibromatosis 1 is one of the most common genetic conditions affecting the nervous system. Individuals with NF1 are predisposed to the development of peripheral nerve sheath tumors (neurofibromas and MPNSTs), astrocytomas (optic pathway gliomas), learning disabilities, seizures, strokes, macrocephaly, and vascular abnormalities. The NF1 tumor suppressor gene encodes a large protein (neurofibromin) that functions primarily as a RAS negative regulator, suggesting that targeted therapy for NF1 might derive from inhibition of the RAS signaling pathway.     

BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants

Recent studies highlight the importance of BRAF alterations resulting in mitogen activated protein kinase (MAK/ERK) pathway activation in low-grade CNS tumors. We studied 106 low-grade CNS neoplasms in a cohort of primarily pediatric patients to identify the prevalence and clinicopathologic significance of these alterations. Polymerase chain reaction testing identified KIAA1549:BRAF fusions in 51 (48%) tumors overall, including 42 (60%) pilocytic astrocytomas, 4 (17%) unclassifiable low-grade gliomas, 4 (36%) low-grade glioneuronal/neuroepithelial tumors, 0 (of 5) pleomorphic xanthoastrocytomas, 0 (of 4) diffuse astrocytomas (World Health Organization grade II), and 1 (of 3, 33%) pilomyxoid astrocytoma. KIAA1549:BRAF gene fusions confirmed by sequencing included the previously reported ones involving exons 1-16/9-18 (49%), 1-15/9-18 (35%), and 1-16/11-18 (8%) and 2 fusions with novel breakpoints: 1-15/11-18 (6%) and 1-17/10-18 (1%). DNA sequencing identified BRAF mutations in 8% of tumors. BRAF mutations were absent. KIAA1549:BRAF fusions were significantly more frequent in infratentorial (57%) and optic pathway (59%) tumors versus supratentorial (19%) tumors (p = 0.001). We did not identify significantly improved progression-free survival in tumors with fusions. In summary, KIAA1549:BRAF fusions predominate in pilocytic astrocytomas but are also present in some low-grade unclassifiable gliomas and glioneuronal tumors. The prognostic and therapeutic significance of this alteration is unclear and merits further study.     

Prolonged survival in adult neurofibromatosis type I patients with recurrent high-grade gliomas treated with bevacizumab

Astrocytic tumors, especially optic pathway pilocytic astrocytomas, are common in pediatric NF1 patients. High-grade gliomas (HGGs) appear to be rare in adult and pediatric NF1 patients. This is a series of five consecutive, adult NF1 patients with recurrent HGGs treated at The University of Texas MD Anderson Cancer Center. Four patients met consensus clinical criteria for NF1 and one patient had presumed segmental NF1. Three patients had glioblastomas, one gliosarcoma, and one progressive, enhancing optic pathway glioma which was not biopsied. Two tumors had molecular testing performed; both were IDH wild type and activating oncogene mutations (1 BRAFV600E and 1 PIK3CA mutation) were found in these tumors. All five patients received bevacizumab-containing regimens at tumor recurrence. The median number of 4-week cycles of bevacizumab was 20. All five patients experienced prolonged post-recurrence survival following bevacizumab treatment ranging from ten to 72 months. The median overall survival from HGG diagnosis was 72.6 months with three patients alive and progression free at last follow-up. Three out of five patients developed vascular complications leading to bevacizumab discontinuation. In this case series, adult NF1 patients with recurrent HGGs had prolonged, post-recurrence survival after treatment with bevacizumab-containing regimens. Based on these results, further study of antiangiogenic therapy in NF1 patients with HGGs and bevacizumab-response in sporadic HGG patients with NF1-mutated tumors is warranted.     

Optico-hypothalamic glioma: an analysis of 16 cases

We reviewed our experience of 16 patients with histologically proven optico-hypothalamic gliomas. They ranged in age from 0.3 to 15 years at the time of diagnosis. Fifteen tumors were located in the optic chiasm, optic nerve, optic tract and/or hypothalamus, while one tumor was confined to one optic nerve. All tumors were classified as low-grade astrocytomas, which were mainly composed of pilocytic astrocytes. No patient had associated neurofibromatosis. The initial treatment for tumors included surgery in 12, radiotherapy in 7, and chemotherapy in 4 patients. After treatment, visual function improved in 3 out of 14, and endocrine function improved in 1 out of 4 evaluable patients. The 5-year actuarial survival rate was 84.0%, and that at 10 years 71.1%. Our experience and the literature indicate that: (1) patients with disease limited to the optic nerve are adequately managed by resection alone; (2) chiasmal-hypothalamic gliomas behave variably, and progressive disease may occur late in the course of the illness; (3) gliomas that arise in patients under 2 years of age and involve the optic chiasm may act aggressively despite their histological benignity; (4) the beneficial effects of radiotherapy occur in about half of the patients; (5) although chemotherapy may be an effective adjuvant treatment modality, it is not an alternative to radiation therapy at present. Both surgery and irradiation therefore offer the best treatment now available for patients with progressive disease.     

中枢神经系统肿瘤CDKN2基因的丢失

目的探讨中枢神经系统肿瘤CDKN2基因的丢失情况。方法采用聚合酶链反应(PCR)对81例脑、脊髓肿瘤手术标本中CDKN2基因的丢失情况进行了检测。结果胶质瘤CDKN2基因丢失率为60％,且高级别胶质瘤基因丢失率显著高于低级别肿瘤;脑膜瘤、神经鞘瘤、垂体腺瘤及转移瘤亦存在不同程度CDKN2基因的丢失。结论CDKN2基因的丢失与中枢神经系统肿瘤的发生、发展有一定的关系。     

Natural history of neurofibromatosis 1-associated optic nerve glioma in mice

Children affected with the inherited tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to the development of low-grade astrocytic optic pathway tumors (optic pathway glioma [OPG]). Previously, we developed a model of NF1-associated astrocytoma (GFAPCre; Nf1(flox/mut) mice) in which mice develop optic nerve and chiasm glioma. To define the molecular pathogenesis of OPG, we used this mouse model to study the natural history of OPG formation using immunohistological and radiographic approaches. We observed that whereas astrocyte hyperplasia is present in the optic nerves associated with gross optic nerve thickening at 3 weeks of age, overt neoplastic changes were not seen until 2 months of age. Astrocyte proliferation was maximal between 3 weeks and 2 months of age, suggesting that the most rapid period of growth occurs early. Mouse OPG tumors were detected by magnetic resonance imaging at 2 months of age and exhibited contrast enhancement, as seen in human OPG. In addition, the mouse OPG tumors exhibited expression of proteins associated with astroglial progenitors, including nestin and brain lipid binding protein. Last, we observed neovascularization and microglial cell infiltration by 3 weeks of age before overt neoplastic transformation, suggesting that these cellular changes participate in the early stages of tumor formation.     

Papillary glioneuronal tumor—a rare entity: report of four cases and brief review of literature

Purpose

Papillary glioneuronal tumors (PGNT) have been recently included as a distinct entity in the WHO classification of tumors of the central nervous system. Their molecular pathogenesis is not clear. In the current study, we present the morphological, immunohistochemical, and molecular features of four cases of PGNT reported over the past 11?years.

Methods

Over a period of 11?years (January 2000–February 2010), there were four cases of PGNT, which were reviewed for histomorphological features. TP53 and IDH1 mutations were assessed using antibodies against p53 protein and for mutant IDH1^R132H protein, respectively. Immunohistochemistry was also performed for epidermal growth factor receptor (EGFR) protein. Fluorescence in situ hybridization assay was used for analyzing 1p/19q deletion status.

Results

All the tumors showed the characteristic biphasic morphology. Rare findings included minigemistocyte-like cells in one, angiomatous areas in three, focal necrosis in one, and a high MIB-1 labeling index of 12 and 13?%, respectively, in two of the cases. All lacked EGFR, IDH1 expression, and 1p/19q deletions. Interestingly, antibody for p53 labeled the tumor cells, mainly those showing glial differentiation, in two cases. At a mean follow-up of 30?months, there was no evidence of disease progression except in one case which recurred after 24?months.

Conclusion

PGNT are rare CNS neoplasms. Despite showing focal morphological features reminiscent of oligodendroglial tumors and presence of astrocytic component, they usually lack the common genetic alterations involved in the pathogenesis of gliomas. Multi-institutional pooling of cases may aid in elucidating their oncogenetic pathway.     

PTEN knockdown with the Y444F mutant AAV2 vector promotes axonal regeneration in the adult optic nerve

The lack of axonal regeneration is the major cause of vision loss after optic nerve injury in adult mammals. Activating the PI3 K/AKT/m TOR signaling pathway has been shown to enhance the intrinsic growth capacity of neurons and to facilitate axonal regeneration in the central nervous system after injury. The deletion of the m TOR negative regulator phosphatase and tensin homolog(PTEN) enhances regeneration of adult corticospinal neurons and ganglion cells. In the present study, we used a tyrosine-mutated(Y444 F) AAV2 vector to efficiently express a short hairpin RNA(sh RNA) for silencing PTEN expression in retinal ganglion cells. We evaluated cell survival and axonal regeneration in a rat model of optic nerve axotomy. The rats received an intravitreal injection of wildtype AAV2 or Y444 F mutant AAV2(both carrying sh RNA to PTEN) 4 weeks before optic nerve axotomy. Compared with the wildtype AAV2 vector, the Y444 F mutant AAV2 vector enhanced retinal ganglia cell survival and stimulated axonal regeneration to a greater extent 6 weeks after axotomy. Moreover, post-axotomy injection of the Y444 F AAV2 vector expressing the sh RNA to PTEN rescued ~19% of retinal ganglion cells and induced axons to regenerate near to the optic chiasm. Taken together, our results demonstrate that PTEN knockdown with the Y444 F AAV2 vector promotes retinal ganglion cell survival and stimulates long-distance axonal regeneration after optic nerve axotomy. Therefore, the Y444 F AAV2 vector might be a promising gene therapy tool for treating optic nerve injury.     

Isocitrate dehydrogenase mutations: a challenge to traditional views on the genesis and malignant progression of gliomas

Isocitrate dehydrogenases (IDHs) convert isocitrate to α-ketoglutarate by oxidative decarboxylation and are thereby involved in multiple metabolic processes. Mutations in the genes encoding IDH1 and IDH2 were first reported in human gliomas in 2008 and later on also identified in a minority of patients with acute myeloid leukemia. The mutations universally affect codons 132 in IDH1 and 172 in IDH2 and result in decreased enzymatic activity. The oncogenic pathway triggered by IDH mutations may involve the activation of hypoxia-inducible factor pathway as well as the acquisition of a novel (gain of enzymatic) function consuming NADPH and generating α-hydroxyglutarate. Most intriguingly, IDH mutations are observed in ～70-80% of grade II/III gliomas and the majority of secondary glioblastomas, but only 10% of primary glioblastomas, suggesting a different cellular origin of the gliomas, which had previously been viewed as a multistep process of malignant progression. Understanding the oncogenic pathway mediated by mutant IDH might result in the development of novel, tailored pharmacological therapies for human glioma patients.     

Central nervous system lymphoma occurring in a patient with neurofibromatosis type 1 (von Recklinghausen disease)

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, which confers an increased risk of a wide range of cancers, and malignant tumors are the most common cause of death in individuals with NF1. Although in children with NF1, the most common neoplasms are optic nerve gliomas and brain tumors, an elevated risk of myeloid leukemia and an increased relative risk of acute lymphoblastic leukemia and non-Hodgkin lymphoma were reported. In adults with NF1, the relative risk of brain tumor is 100 times higher than in the general population. Cases of malignant lymphoma occurring in NF1 adult patients have been reported. However, the association between NF1 and lymphoproliferative diseases is still debated. We report a case of CNS primitive lymphoma in an adult patient who resulted positive for NF1 at genetic testing. At present, only one case of CNS lymphoma in an adult patient displaying clinical criteria for NF1 diagnosis has been reported.     

Insights into optic pathway glioma vision loss from mouse models of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of the oncoprotein RAS and controls cell growth and survival. Individuals with NF1 are prone to developing low-grade tumors of the optic nerves, chiasm, tracts, and radiations, termed optic pathway gliomas (OPGs), which can cause vision loss. A paucity of surgical tumor specimens and of patient-derived xenografts for investigative studies has limited our understanding of human NF1-associated OPG (NF1-OPG). However, mice genetically engineered to harbor Nf1 gene mutations develop optic gliomas that share many features of their human counterparts. These genetically engineered mouse (GEM) strains have provided important insights into the cellular and molecular determinants that underlie mouse Nf1 optic glioma development, maintenance, and associated vision loss, with relevance by extension to human NF1-OPG disease. Herein, we review our current understanding of NF1-OPG pathobiology and describe the mechanisms responsible for tumor initiation, growth, and associated vision loss in Nf1 GEM models. We also discuss how Nf1 GEM and other preclinical models can be deployed to identify and evaluate molecularly targeted therapies for OPG, particularly as they pertain to future strategies aimed at preventing or improving tumor-associated vision loss in children with NF1.     

人脑胶质瘤PTEN基因变异的研究

目的进一步了解PTEN基因突变和缺失在人脑胶质瘤发生和恶性进展中的作用。方法应用聚合酶链反应-单链构象多态性(PCR-SSCP)结合银染技术和双重PCR分别检测10例正常脑组织、10例脑膜瘤、80例胶质瘤PTEN基因第5和第8外显子区域上的突变与缺失情况。结果发现10例正常脑组织和10例良性脑膜瘤均无PTEN基因点突变发生,80例胶质瘤分别有11例(13.75%)和27例(33.75%)发生基因点突变和基因缺失,且PTEN基因失活与星形细胞瘤病理分级明显相关(P<0.05),其中高恶性度胶质瘤(III、IV级)突变率(24.44%)和缺失率(60%)明显高于低恶性度(I、II级)胶质瘤(P<0.05)。结论PTEN基因突变或缺失与胶质瘤病理分级关系密切,可能属于胶质瘤恶性进展的后期事件。     

Optic pathway gliomas in children with and without neurofibromatosis 1

Optic pathway gliomas represent 2 to 5% of brain tumors in children. Frequently asymptomatic, sometimes they demonstrate rapid growth, causing considerable visual dysfunction, neurologic deficits, and endocrine disturbances. Most optic pathway gliomas are diagnosed in patients with neurofibromatosis 1. Little is known about their natural course; therefore, there are no clear and widely accepted guidelines for their treatment. This study compared the clinical manifestations and natural history of sporadic and neurofibromatosis 1-associated optic pathway gliomas with regard to age at diagnosis, gender, and findings on neurologic, ophthalmologic, and neuroradiologic examinations in 83 children with optic pathway gliomas: 51 children with neurofibromatosis 1 and 32 children without any symptoms or signs of neurofibromatosis 1. A prospective study was performed in 21 patients with neurofibromatosis 1. In the rest of the patients with neurofibromatosis 1 and in 32 children with sporadic tumors, the analysis was carried out retrospectively. There was an increased incidence of females in the group of patients with neurofibromatosis 1 with optic pathway gliomas compared with the entire group of patients with neurofibromatosis 1 remaining for follow-up (P = .013). All optic pathway gliomas were found in children below 10 years of age, slightly earlier in the group without neurofibromatosis 1 (median age 4.6 vs 4.8 years). Children with optic pathway gliomas associated with neurofibromatosis 1 had predominantly multifocal lesions (P = .0001), whereas in the group without neurofibromatosis 1, isolated chiasmal involvement was more common (P = .002). Children with sporadic gliomas had significantly more frequently increased intracranial pressure, decreased visual acuity, and abnormalities of fundus of the eye at the time of diagnosis. The radiologic progression, visual deterioration, and endocrinologic complications were documented on follow-up more commonly in children with sporadic tumors. Our findings support the concept that there is an earlier and more severe clinical presentation of optic pathway gliomas in children with sporadic tumors than in those associated with neurofibromatosis 1.     

Recent advances in neurofibromatosis type 1

PURPOSE OF REVIEW: The past decade, since the identification of the neurofibromatosis type 1 (NF1) gene, has witnessed great advances in our understanding of the role of the NF1 gene in the molecular pathogenesis of NF1-associated clinical abnormalities. The purpose of this review is to highlight recent advances in defining the molecular etiology of nervous system tumors and learning disabilities. RECENT FINDINGS: Neurofibromas and optic pathway gliomas result from NF1 inactivation in Schwann cells and astrocytes, respectively, but other cellular factors contribute to tumorigenesis. In addition, malignant progression of plexiform neurofibromas to malignant peripheral nerve sheath tumors requires additional genetic changes, including increased expression of growth factor receptors, molecules that are involved in tumor invasion and metastasis, and inactivation of critical cell cycle regulators. In addition, specific types of NF1 gene mutation may be associated with an increased risk for malignancy in individuals with NF1. SUMMARY: Research over the past few years has resulted in a detailed understanding of the molecular genetics of benign and malignant tumors affecting individuals with NF1 as well as the development of refined small animal models for these tumors. In addition, clinical studies have begun to define specific subpopulations of patients at risk for cancer and have identified targeted therapies for NF1-associated tumors, based on basic science research advances.     

Efficacy and complications of radiotherapy of anterior visual pathway tumors

A progressive disturbance in visual acuity or visual field, along with an unexplained optic nerve atrophy, suggests the possibility of a tumor. Tumors that frequently affect the anterior visual pathway include primary optic nerve sheath meningiomas, intracranial meningiomas, optic gliomas, pituitary tumors, and craniopharyngiomas. The location of these tumors sometimes prohibits a complete surgical excision that might jeopardize the visual system. Radiation therapy, however, can be beneficial in these cases. This article reviews the indications for radiotherapy of tumors that involve the anterior visual pathway, along with the possible complications. Cases that present the effect of radiation therapy and radiation damage are presented.     

The role of surgical biopsy in the diagnosis of glioma in individuals with neurofibromatosis-1

Most gliomas in neurofibromatosis type 1 (NF1) are pilocytic astrocytomas (PAs) of the optic pathway occurring in young children. However, some individuals develop gliomas that lack the typical NF1-associated clinical features or radiographic appearance. We identified 17 atypical presentations from a review of 100 patients with NF1-associated gliomas. Biopsy showed that 9 were not classic PAs. These data highlight the value of biopsy in NF1-associated gliomas with unusual clinical or radiographic presentations.     

Brain gliomas,hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1

PurposeTo evaluate the incidence and clinical importance of brain gliomas – optic pathway gliomas (OPGs) and especially gliomas outside the optic pathway (GOOP) for children with neurofibromatosis type 1 (NF1), additionally, to assess the causes of obstructive hydrocephalus in NF1 children with an emphasis on cases caused by idiopathic aqueduct stenosis.Subjects and methodsWe analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery.ResultsWe have found OPGs in 77/285 (27%) children and GOOPs in 29/285 (10,2%) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30,5%). GOOPs were significantly more often treated than OPGs (p > 0.01). OPGs contain clinically important subgroup of 14/285 (4.9%) spreading to hypothalamus. Spontaneous regression was documented in 4/285 (1.4%) gliomas and the same number of NF1 children died due to gliomas.Obstructive hydrocephalus was found in 22/285 (7.7%) patients and 14/22 cases were due to glioma. Idiopathic aqueduct stenosis caused hydrocephalus in 6/22 cases and was found in 2.1% of NF1 children. Two had other cause.ConclusionsThe total brain glioma number (OPGs and only GOOPs together) better reflected the overall brain tumour risk for NF1 children. However, GOOPs occur less frequently than OPGs, they are more clinically relevant. The obstructive hydrocephalus was severe and featuring frequent complication, especially those with GOOP. Idiopathic aqueduct stenosis shows an unpredictable cause of hydrocephalus in comparison with glioma and is another reason for careful neurologic follow up.     

Clinical features and pathobiology of neurofibromatosis 1

Neurofibromatosis 1 is a progressive multisystem disorder. The hallmark feature is the occurrence of nerve sheath tumors, neurofibromas. Other features include tumors such as optic gliomas and malignant peripheral nerve sheath tumors. There are also nontumor manifestations, such as skeletal dysplasia and learning disabilities. Since the NF1 gene was identified, much has been learned about the molecular genetics of the disorder; recently, this has led to insights about pathogenesis. Ultimately, it is hoped that this will be translated into specific means of treatment. This review describes the various clinical features of neurofibromatosis 1 and considers them in the context of the pathophysiology of the disorder.