Base substitutions at A:T pairs constitute an important fraction of ESC p53 mutations, in contrast to mutation patterns in most other types of solid tumors.
Overall, it is demonstrated that alterations of the p53 gene might be involved in the pathogenesis or progression of at least some human leukemias, although the alterations in leukemias seemed to be not as frequent as in solid tumors.
The results of a phase I clinical trial of the topoisomerase I (Topo I) poison CPT-11 followed by the cyclin-dependent kinase inhibitor flavopiridol in patients with advanced solid tumors indicate that patients whose tumors were wild-type, but not mutant, for p53 obtained the most clinical benefit from this combination therapy.
In solid tumors, p53 antibodies are found in 30% of the patients with p53 mutations, and their analysis is an interesting method for the detection of p53 mutations.
An identical p53 mutation was invariably present in all samples from primary and metastatic colorectal tumor biopsies within the same patient. p53 mutations were detected in peripheral blood from 8 of these 19 patients with p53-mutated solid tumors.
These studies showed that TP53 and PI3KCA are the two most mutated genes in all types of cancers and that 30-70% of all solid tumors harbor potentially 'actionable' mutations that can be exploited for patient stratification or treatment optimization.
In this study, we investigated GSTM1, GSTT1 and p53 codon 72 polymorphisms in a variety of human tumor cell lines originating from different organs to clarify tissue-specific polymorphic frequency of these genes in human solid tumors.
In pediatric solid tumors, such as neuroblastoma (NB), it has been reported that the frequency of TP53 gene alterations is lower than that in adult tumors, suggesting that other tumor suppressor genes may play more important roles in the development of pediatric solid tumors.
Mutations of the p53 gene on exons 5 through 8 were examined in 82 childhood malignant solid tumors by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method, and the nature of these mutations was confirmed by direct sequencing.
In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible.
In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively.
Thus, disruption of regulated p53 expression resulting in lack of detectable p53 mRNA even by RT-PCR occurs in about 30% of cases of AML; however, p53 alterations typical for human solid tumors are an infrequent event in most types of human acute leukemias.
With a technique we recently developed for the analysis of p53 mutations in genomic DNA from tumor cell clusters in touch preparations of solid tumors, we sequenced exons 5-9 and adjacent splice junctions of the gene in 44 breast cancers.
The frequency of p53 alterations when comparing breast CIS with and without an invasive component indicated that p53 mutations usually occur before invasion during the progression of breast cancer, as is observed for a number of other adult solid tumors.