Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Most arise in the cerebellum, but they also can develop in the brainstem and optic nerve, where gross total resection (GTR) is not possible. In the absence of GTR, significant variability in both clinical behavior and histology exists. To identify potential markers associated with poor clinical outcome, we retrospectively assessed pathological features in 107 patients with PAs. We identified four pathological features (necrosis, oligodendroglioma-like features, vascular hyalinization, and calcification) that showed a significant correlation with decreased event-free survival (EFS). Similar to previous reports, we also found that PAs involving the optic pathway were associated with worse EFS compared with those arising in other locations. In contrast, mitotic index, p53 immunoreactivity and hyperactivation of several mitogenic signaling pathways (MAPK, CREB, mTOR) did not demonstrate a statistically significant relationship with EFS. Lastly, we did find a statistical trend between EFS and the number of CD68+ cells, suggesting that non-neoplastic elements of the tumor microenvironment may influence subsequent growth and clinical recurrence. Collectively, the identification of specific histopathologic features associated with clinical outcome may improve our ability to determine which PAs are more likely to exhibit clinical progression and require more vigilant observation.
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PMID:Histopathologic predictors of pilocytic astrocytoma event-free survival. 1927 Dec 26

Pilocytic astrocytoma (PA) is the most common glioma in the pediatric population. PAs can exhibit variable behavior that does not always correlate with location, yet at present there is no way to predict which tumors will be more aggressive. To address this problem, an institutional cohort of 147 PAs (118 with outcome data) from both cerebellar and noncerebellar locations (spine, diencephalon, midbrain, brainstem and cortex) was utilized. Parameters included quantification of characteristic morphologic variables as well as genes previously shown to be of relevance in high-grade gliomas, including MIB-1, p53 and MGMT. In this cohort, the classic biphasic appearance was most common in cerebellar tumors, whereas noncerebellar tumors were predominantly microcystic. Associations with outcome suggest that the presence of degenerative atypia may be a favorable factor in PAs. Oligodendroglial morphology and the absence of leptomeningeal invasion are adverse histologic factors, but only in cerebellar tumors. Conversely, MIB-1 proliferation index and p53 and MGMT expression do not correlate with outcome. Morphologic biomarkers thus do exist for PAs, but the utility of each biomarker varies according to location. These results suggest that PAs differ fundamentally according to location; therefore, biological behavior may not simply depend on extent of resection.
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PMID:Impact of morphology, MIB-1, p53 and MGMT on outcome in pilocytic astrocytomas. 1983 38

Pilocytic astrocytoma (PA) is the most common pediatric tumor, with the vast majority being benign (WHO Grade I). Herein, we present a rare sporadic (not radiation- or NF1-associated) anaplastic PA arising from the cerebellum of an adult patient. The diagnosis was based on the coexistence of classic PA and more cellular foci, associated with both tumor necrosis and up to 27 mitoses per 10 high power fields. Based on these features, the tumor was felt to be equivalent in biological behavior to that of a WHO Grade III astrocytoma. Additional genetic studies revealed the presence of a BRAF V600E mutation. In comparison to the foci of classic PA, the malignant component showed increased p53 protein expression, decreased p16 protein expression, and hemizygous p16 gene deletion by FISH analysis. This case provides additional support for the concept of anaplastic transformation in PA and further elucidates the possible molecular pathways associated with malignant progression.
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PMID:Adult with cerebellar anaplastic pilocytic astrocytoma associated with BRAF V600E mutation and p16 loss. 2319

It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.
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PMID:Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population. 2695 5

Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed.The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses.In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival (p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism.The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan.
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PMID:TP53 codon 72 polymorphism may predict early tumour progression in paediatric pilocytic astrocytoma. 2737 6

Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed. We transduced the PA short-term culture DKFZ-BT66 derived from the PA of a 2-year old patient with a doxycycline-inducible system coding for Simian Vacuolating Virus 40 Large T Antigen (SV40-TAg). SV40-TAg inhibits TP53/CDKN1A and CDKN2A/RB1, two pathways critical for OIS induction and maintenance. DNA methylation array and KIAA1549:BRAF fusion analysis confirmed pilocytic astrocytoma identity of DKFZ-BT66 cells after establishment. Readouts were analyzed in proliferating as well as senescent states, including cell counts, viability, cell cycle analysis, expression of SV40-Tag, CDKN2A (p16), CDKN1A (p21), and TP53 (p53) protein, and gene-expression profiling. Selected MAPK inhibitors (MAPKi) including clinically available MEK inhibitors (MEKi) were tested in vitro. Expression of SV40-TAg enabled the cells to bypass OIS and to resume proliferation with a mean doubling time of 45h allowing for propagation and long-term culture. Withdrawal of doxycycline led to an immediate decrease of SV40-TAg expression, appearance of senescent morphology, upregulation of CDKI proteins and a subsequent G1 growth arrest in line with the re-induction of senescence. DKFZ-BT66 cells still underwent replicative senescence that was overcome by TERT expression. Testing of a set of MAPKi revealed differential responses in DKFZ-BT66. MEKi efficiently inhibited MAPK signaling at clinically achievable concentrations, while BRAF V600E- and RAF Type II inhibitors showed paradoxical activation. Taken together, we have established the first patient-derived long term expandable PA cell line expressing the KIAA1549:BRAF-fusion suitable for preclinical drug testing.
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PMID:Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. 2800 90

Pilocytic astrocytoma is a slowly growing neoplasia that represents the most frequent cerebral tumor in pediatric age. Malignant transformation is rare and it is usually related to previous radiotherapy. The authors describe a case of a spontaneous malignant transformation of a pilocytic astrocytoma. A 3-year-old boy was diagnosed with a cerebellar hemisphere tumor. He was submitted to a complete excision of the lesion, and histological findings were consistent with pilocytic astrocytoma. It was negative for p53. Twelve years later he presented with a local recurrence. Histopathological diagnosis was glioblastoma and it was positive for p53. Death from disease progression occurred 16 months after the diagnosis of glioblastoma. This case suggests that patients with pilocytic astrocytoma need closer follow-up and further genotypic studies in order to provide clues to clinical behavior. Such understanding can allow us to stratify treatment accordingly and to proceed to more aggressive treatment when necessary.
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PMID:Spontaneous Malignant Transformation of a Pilocytic Astrocytoma of Cerebellum: Case Report. 2850 86