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.
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%).
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).
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.
Germ-line mutations of the tumor-suppressor gene p53 have been observed in some families with the Li-Fraumeni syndrome (LFS), a familial cancer syndrome in which affected relatives develop a diverse set of early-onset malignancies including breast carcinoma, sarcomas, and brain tumors.
Germ-line p53 mutations are associated with dominantly inherited Li-Fraumeni syndrome (LFS), which features early-onset sarcomas of bone and soft tissues, carcinomas of the breast and adrenal cortex, brain tumors, and acute leukemias.
The observation that somatic p53 mutations in sporadic brain tumours are largely restricted to those of astrocytic origin and that astrocytomas also prevail among CNS neoplasms associated with p53 germline mutation strongly suggests, that p53 mutations are capable of initiating neoplastic transformation in astrocytes of the human nervous system.
Finally, while data on the p53 gene and protein studies in human brain tumors are accumulating rapidly, the clinical significance of such data remains unclear.
To prove these data, the authors screened a series of 42 astrocytic human brain tumors with a relatively high proportion (16.6%) of the pilocytic variant for the presence of p53 mutations, using the polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis, followed by DNA sequencing.
We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements.
By removing alkyl groups from the O6-position in guanine, MGMT can prevent G:C to A:T transition mutations, a type of variation frequently involving TP53 mutations in brain tumors.
Germline TP53 mutations predispose to a rare familial cancer syndrome, the Li-Fraumeni Syndrome (LFS), characterized by the early onset of multiple cancers including childhood adrenocortical carcinomas, sarcomas and brain tumors, and breast and colon cancer in young adults.
Initially, a TP53 gene germline missense mutation was detected in an 11-year-old kindred with acute myeloid leukaemia (AML) following intensive treatment of a brain tumour.