Finally, loss of APE1 in combination with p53 inactivation resulted in a profound susceptibility to brain tumors, including medulloblastoma and glioblastoma, implicating oxidative DNA lesions as an etiologic agent in these diseases.
We investigated TP53 mutations in exons 2-11 by denaturing high performance liquid chromatography (DHPLC) and sequencing, and p53 accumulation by immunohistochemistry in brain tumour of the 30 patients from CEREPHY study with a history of occupational exposure to pesticides (n = 21) and/or organic solvents (n = 14) for whom tumoral tissue was available.
Germline mutations of the p53 coding region are present in approximately 50-70% of patients with Li-Fraumeni Syndrome (LFS), a rare hereditary disorder of familial and intraindividual clustering of different malignancies such as sarcoma (index tumor), breast cancer, brain tumors, leukemias, and adrenocortical carcinomas, the latter usually in young children.
Moreover, Ad-mΔ19/p53VPΔ30 showed a greater antitumor effect and increased survival rates of mice with U343 brain cancer xenografts that expressed wild-type p53 and high Mdm2 levels.
The incidence rate of brain tumors corresponded to every p53-coding exon for single-strand conformation polymorphisms (SSCP) and the mutations were confirmed by sequencing. p53 mutations were found in 2 of 10 glioblastomas (20%) and in 1 of 8 low-grade astrocytomas (12.5%).
The aim of this study was to determine the relation of HIF-1alpha to vascular endothelial growth factor (VEGF; an important angiogenic molecule in brain tumours), p53 expression, angiogenesis, proliferative potential and clinical outcome in a large series of diffuse astrocytomas.
Brain tumors were associated with missense TP53 mutations located in the DNA-binding loop that contact the minor groove of DNA (P = 0.01), whereas adrenal gland carcinomas were associated with missense mutations located in the loops opposing the protein-DNA contact surface (P = 0.003).
We conclude from these findings that p53 gene mutations in brain neoplasms are primarily limited to tumors of astrocytic origin and that the p53 gene mutations in sporadic astrocytomas are somatic in origin (i.e., nonprenatally determined).
This review outlines the uses of adenoviruses in brain tumor therapy by examining clinical trials of adenovirus-mediated p53 gene therapy and by reviewing the application of two conditionally replicative adenoviruses (CRAds) ONYX-015 and Delta 24 in brain tumors.
Loss of the tumor suppressor gene p53 and its encoded protein are the most common genetic events in human cancer and are a frequent occurrence in brain tumors. p53 functions as a transcription factor and is responsible for the transactivation and repression of key genes involved in cell growth, apoptosis and the cell cycle.
Others have also associated the virus to the induction of colon cancer and aneuploid brain tumors by producing a highly tumorigenic protein named T antigen (TAg), which binds to beta-catenin and inactivates key proteins such as p53.
High levels of p53 have been detected in the serum of colon cancer patients, although p53 protein has not been detected in the serum of brain tumor patients.
To test the hypothesis that mutations of the p53 tumor suppressor gene in human tumors also can correlate with the response to chemotherapy, p53 mutations2 were identified in primary human malignant brain tumors and cell lines in which AT activity and procarbazine sensitivity in a xenograft model was ascertained.
Inclusion criteria were 1. family history of breast cancer; 2. absence of germline BRCA1 and p53 mutation; and 3. at least one case of brain tumour (glioblastoma, meningioma, or medulloblastoma) in either the index case or one of their first or second degree relatives.
Overexpression of p21 enhanced clonogenic survival and suppressed apoptosis after gamma-irradiation in human brain tumor cell lines with or without p53 protein deficiency.