However, there is one example of germ-line mutation of p53 gene (the deletion of the codon 236) that is associated with a familiar brain tumor syndrome.
Thus, in vitro and in vivo data suggest the loss of important tumor-suppressing functions and demonstrate a dominant negative effect of this unique p53 mutant that is associated with an unusual clustering of familial brain tumors.
Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors.
The analysis of 475 tumors in 91 families with p53 germline mutations reported since 1990 shows that breast carcinomas are most frequent (24.0%), followed by bone sarcomas (12.6%), brain tumors (12.0%), and soft tissue sarcomas (11.6%).
Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.
Nearly all brain tumors develop following the progressive accumulation of genetic alterations of oncogenes and tumor suppressor genes (such as p53 and retinoblastoma protein).
Thus, the histological progression of brain tumours was associated with a clonal expansion of cells that had previously acquired a mutation in the p53 gene, endowing them with a selective growth advantage.
To test whether prevalence and types of alterations in the p53 pathway in brain tumor development may explain some of this difference in risk, we have analyzed the p53 status of astrocytic gliomas from a population-based sample of cases within our San Francisco Bay Area Adult Glioma Study.
Human malignant gliomas (glioblastomas and anaplastic astrocytomas) are the most frequent brain tumors and are associated with a variety of genetic alterations including retinoblastoma (RB) and p53 gene mutations, loss of interferon alpha and beta (IFNA, IFNB) genes and lack of O6-methylguanine-DNA methyltransferase (MGMT) expression.
The authors here present a family with pR337P mutation in TP53 gene who had a child with acute lymphoblastic leukemia (ALL) and associated adrenocortical carcinoma as a case 1 and his cousin with brain tumor as a case 2.
More rarely, it occurs in the Li-Fraumeni syndrome, caused by a p53 germline mutation, in which markedly early-onset BC is found in association with brain tumors, sarcomas, leukemia, lymphoma, malignant melanoma, and adrenal cortical carcinoma.
Our results demonstrate the utility of the p53 functional assay for studies of clonality and support the hypothesis of clonal progression of brain tumors in vivo.
Overexpression of p21 enhanced clonogenic survival and suppressed apoptosis after gamma-irradiation in human brain tumor cell lines with or without p53 protein deficiency.
A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms.
Although not widely accepted, it is possible that different mutations of the p53 gene in patients with brain tumors may imply a different ultimate prognosis.
Human astrocytic brain tumors select for mutations in the p53 tumor suppressor gene early in malignant progression. p53 is activated upon various kinds of cellular stress leading to apoptosis or cell cycle arrest, but is also implicated in complex biological processes such as inhibition of angiogenesis and metastasis.