We examined TP53 status in relation to telomere maintenance mechanism (TMM) in 108 patients with glioblastoma multiforme and two patients with anaplastic astrocytoma from New Zealand and United Kingdom.
Proteomic investigation of glioblastoma cell lines treated with wild-type p53 and cytotoxic chemotherapy demonstrates an association between galectin-1 and p53 expression.
When compared with the histological grading, the rates of OS for Tel 17p and p53 in anaplastic astrocytomas were higher than those of glioblastomas, suggesting that the deletion may be associated with the early events in tumorigenesis and that some glioblastomas without chromosome 17 aberrations may be independent from tumour progression via low-grade gliomas.
NGS data obtained in a retrospective analysis of 121 gliomas allowed for their molecular classification into distinct biological groups, including (i) isocitrate dehydrogenase gene (IDH) 1 or 2 mutant astrocytic gliomas with frequent α-thalassemia/mental retardation syndrome X-linked (ATRX) and tumor protein p53 (TP53) gene mutations, (ii) IDH mutant oligodendroglial tumors with 1p/19q codeletion, telomerase reverse transcriptase (TERT) promoter mutation and frequent Drosophila homolog of capicua (CIC) gene mutation, as well as (iii) IDH wildtype glioblastomas with frequent TERT promoter mutation, phosphatase and tensin homolog (PTEN) mutation and/or epidermal growth factor receptor (EGFR) amplification.
We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies.
We examined 32 primary glioblastomas, treated with radiotherapy and surgery, for TP53 mutation by direct sequencing and MGMT promoter methylation by methylation-specific PCR.
In order to assess TP53 deleted cells in de novo GBM quantitatively, we performed dual color fluorescence in situ hybridization (FISH) for TP53 and centromere 17 in nine cases of de novo GBM with frozen surgical materials.
These results suggest that MDM2 overexpression with or without gene amplification constitutes a molecular mechanism of escape from p53-regulated growth control, operative in the evolution of primary glioblastomas that typically lack p53 mutations.
We measure clonogenic radiosensitivity in 39 human tumor cell lines that vary in histological type (colorectal, glioblastoma, prostate, bladder, teratoma, breast, melanoma and liver) and expression of several genes purported to influence radiosensitivity: ATM (ataxia telangiectasia mutated), TP53 (tumor protein 53), CDKN1A (cyclin-dependent kinase N1A), 14-3-3sigma (an isoform of the 14-3-3 gene) and DNA mismatch repair genes .
Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.
The pediatric GBMs should also be investigated for MGMT promoter methylation to identify a subset of patients likely to benefit from TMZ therapy. p53 protein overexpression was more common in pediatric primary GBMs.
The glioblastoma contained 95% mutant p53 alleles, whereas blood from the patient and her parents contained only normal background levels of red colonies.
Mutation of PTEN, amplification of EGFR, and loss of the q arm of chromosome 10 were statistically significantly less common in anaplastic astrocytoma than in glioblastoma multiforme (P =.033, P =.001, and P<.001, respectively), and mutation of p53 was statistically significantly more common (P<.001).
In this study we investigated Bcl-6 translocation and its transcriptional and translational levels in formalin-fixed, paraffin-embedded cerebral tissue sections from glioblastoma (GBM), low-grade glioma (Astrocytoma grade II and III), and meningioma patients, and correlated them with apoptotic processes and p53 and caspase-3 expression.
Tissue samples were used to determine EGFR, PTEN, and 1p and 19q status by fluorescence in situ hybridization (FISH); p53 and mutant IDH1 protein expression by immunohistochemistry (IHC); and MGMT promoter status by methylation-specific polymerase chain reaction (PCR).GBM-Os accounted for 11.9% of all GBMs.
In contrast, malignant anaplastic astrocytomas and glioblastoma multiforme have abnormalities similar to those seen in adults, including loss of alleles on 17p13 and TP53 mutations, trisomy 7, EGFR rearrangements, and loss of chromosomes 10 and 22.
Here, we demonstrate deletion and truncation of both p53 alleles in a primary human glioblastoma and a derived cell line as the combined result of a t(17;20) reciprocal translocation and a 1.1 Mbp genomic deletion on chromosome 17p, starting in intron 4 of the p53 gene and ending at the telomeric CA-repeat marker D17S960.
Our results reveal that the loss of p53 combined with oncogene overexpression in mature astrocytes simulates pivotal features of glioma pathogenesis, providing a good model for assessing the development of secondary glioblastomas.
In addition, 1pLOH and TP53 mutations in gliomas may be markers of oligodendroglial and astrocytic pathways, respectively, which may separate gliomas with the same histological diagnosis, especially oligodendroglial tumors and glioblastomas.
Understanding mutant p53 functions led to the development of novel approaches to restore p53 activity or promote mutant p53 degradation for future GBM therapies.
The strikingly high incidence of TP53 mutations and the relative absence of other genetic alterations groups gcGBM together with a previously recognized molecular genetic variant of GBM (type 1 GBM).