In the present meta-analysis, we aimed to elucidate the associations of TP53rs1042522 genetic polymorphism with the risk of osteosarcoma or Ewing sarcoma.
Ewing sarcoma (ES), a common pediatric primary bone neoplasm, has a well-defined genomic landscape with various predisposing genomic elements including TP53, PMS2 and RET.
Additionally, RNA was extracted from the CTCs for molecular analysis including demonstration of an EWS-FLI1 translocation, identification of a previously unrecognized p53 mutation in a patient with Ewing sarcoma, and single cell RNA sequencing of CTC from a child with alveolar rhabdomyosarcoma.
A growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma.
We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells.
As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients.
Here, we show that the small molecule reactivation of p53 and induction of tumor cell apoptosis (RITA, NSC652287) is highly effective in reducing growth and tumorigenic potential of Ewing sarcoma cell lines.
In concordance with a role of PIG3 protein for cell death, we showed residual apoptotic activity of p53-C277Y to which the described Ewing's sarcoma cell line was found to be resistant. p53-C277Y has previously been reported to bind to DNA with altered sequence specificity and to be unable to activate generic p53 target genes in yeast-based functional assays.
These data support a role for p53 as a tumor suppressor in Ewing's sarcoma and demonstrate the use of transcriptional profiling of model systems in the identification of cooperating mutations in human cancer.
While TP53 abnormalities were far more frequent in osteosarcoma than in Ewing sarcoma, alterations of p16INK4, p14ARF, and p15 were present at similar frequencies in the two types of sarcoma.
In this study, we analyzed the frequency of p53 tumor suppressor gene mutation in exons 4-8 by PCR-SSCP and direct sequencing, and the expression of p53-protein in Ewing's sarcoma (ES) by using immunohistochemistry.
As the molecular events leading to the development of pediatric bone sarcomas remain unclear, we analyzed 75 osteosarcoma and Ewing sarcoma samples from 43 pediatric patients to search for alterations at the TP53 or p16INK4 tumor suppressor genes.
Published studies have included few cases of Ewing's sarcoma (ES) or peripheral neuroectodermal tumour (PNET), a tumour group in which alterations of the p53 pathway have so far not been extensively studied.
Our findings suggest that mutations of the p53 gene in ES might represent late genetic events related to tumor progression, and that aberrations of the p53 gene might not be involved in the development or the progression of NB.