The most common predisposition syndromes include germline TP53 mutations and constitutive alterations in RAS pathway activation, such as Costello syndrome, Noonan syndrome and neurofibromatosis type 1.
Such changes, among others, include hemizygous alterations of the neurofibromatosis 1 (NF1) and p53 genes that are involved in apoptotic pathways, and alterations in multiple DNA repair genes such as mismatch repair (MMR) genes, x-ray cross-complementary genes (XRCC), and O6-methylguanine-DNA methyltransferase (MGMT) genes.
We show that patient-derived GBM and NF1 malignant peripheral nerve sheath tumor (MPNST) lines, as well as tumor lines derived from the Nf1-/+;Trp53-/+ (NPcis) mouse model of astrocytoma and MPNST are highly sensitive to inhibition by schweinfurthin A and its synthetic analogs.
Modifiers in the genetic background affect the severity of the disease and we have previously mapped two modifier loci, Nstr1 and Nstr2, that influence resistance to PNSTs in the Nf1-/+;Trp53-/+cis mouse model of NF1.
Coinactivation of the TP53 gene by deletion, or by point mutation along with NF1 gene inactivation, is known to exacerbate disease symptoms in NF1, therefore TP53 gene inactivation was screened.
Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies.
We suggest that alterations in the p53 and RB pathway, both are essential in controlling the cell-cycle progression, are critical points in the tumorigenesis of sporadic and NF1-associated MPNSTs, whereas the PTEN gene seems to play no significant role in this process.
Thus, we investigated the occurrence of TP53 and p16(INK4A) gene deregulation and the presence of microsatellite alterations at markers located at 17p, 17q, 9p21, 22q, 11q, 1p, or 2q loci in MPNSTs and neurofibromas either related (14 cases) or unrelated (14 cases) to NF1.
However, topographic intratumor heterogeneity results from the accumulation of genetic lesions in tumor suppressor genes, predominantly neurofibromatosis (NF)-1-defective in the superficial compartment and tumor protein p53 (TP53)-defective in the deep one, with lower proliferation and down-regulation of apoptosis in the latter.
Mutations in the NF1 and TP53 genes have been found in some MPNSTs, and recent data from mouse models support a synergistic effect of these two genes in the development of MPNST.
This was confirmed by loss of heterozygosity for p53 in the non-NF1 patient, suggesting that p53 is involved in both hereditary and sporadic Triton tumors.
All primary tumors were histologically diagnosed as pilocytic astrocytoma (WHO grade I), except for one anaplastic pilocytic astrocytoma (WHO grade III) which developed in an NF1 patient and recurred as glioblastoma multiforme (WHO grade IV). p53 mutations were detected using an assay in yeast which tests the transcriptional activity of p53 proteins synthesized from tumor mRNA-derived p53-cDNA templates.
A germline mutation in the NF1 gene and sequential inactivation of p53 alleles in the malignant clone of JCML raise the possibility of a correlation between NF1 and p53 genes in the tumorigenesis of JCML.
Adjustment for local radiation dose and exclusion of patients known to be predisposed to SMN (carriers of p53 mutation and those with Recklinghausen's disease) did not affect this risk substantially.
Previous studies from our laboratory demonstrated increased levels of wild type p53 protein in skin fibroblasts (SF) of patients from heritable cancer syndrome, including familial adenomatous polyposis (FAP), neurofibromatosis type 1 (NF1), and bilateral retinoblastoma (bRB) (Kopelovich and DeLeo, 1984,1986).
Inherited mutations of the p53 and neurofibromin genes are thought to cause two distinct neoplastic disorders in which gliomas occur, the Li-Fraumeni syndrome and neurofibromatosis type 1.
In addition, there is evidence suggesting a contribution for the p53 and NF1 tumor-suppressor genes, and the nm23 metastasis-suppressor gene, in melanoma development or progression.