Structure and function of p53 in normal cells and their aberrations in cancer cells: Projection on the hematologic cell lineages

Abstract

In this review, we have reported on the distribution of genetic alterations detected in the various hematologic malignancies. In addition to the 235 specific point mutations scored, gross changes in the structure of p53 were also reported. Figure 3 represents a summary of the distribution of the 235 p53 mutations detected in a variety of hematologic fresh samples and established cell lines. This group includes the following malignancies: ALL, AML, ATCL, B-CLL, CML, lymphoma, MDS, and MM. Analysis of the various genetic events led us to the following generalizations. (1) The majority of point mutations map to conserves regions II-V (mainly to conserved region IV and V). The dinucleotide CpG, although underrepresented in DNA, is a hot spot and accounts for 34% (79/235) of events in hematologic malignancies. More than 86% of these were transitions from G to A or C to T transitions, respectively. These results are in agreement with those reported in the literature. CpG dinucleotides are preferentially involved in spontaneous mutations and result from methylation-induced deamination of 5 methyl cytosine. The remaining mutations are relatively evenly distributed between G:C (scored after subtraction of mutations occurring at CpG) and A:T, with a slight preference of G or C basepair in MDS and lymphoma patients. Of note are frequent G:C to A:T transitions, not localized in CpG in cases of MM patients (7/14 patients). These genetic changes were reported to be induced by DNA damaging agents. (2) The most common mutations are transitions (in which purine is substituted for a purine or a pyrimidine for a pyrimidine) followed by transversions (in which a purine is substituted for a pyrimidine or vise versa) and deletions/insertions. (3) Arginine is a preferential target of the mutations (76 times), mainly at the following codons: 248, 273, 175, 213, 282. Because arginine is frequently coded by CGN, it is not surprising that this amino acid is a preferential target of spontaneous mutations. Additional amino acids that are frequent targets for mutations are glycine, aspartic acid, aspargine, methionine, and cysteine, which are hit at the following codons, respectively: 245, 281, 239, 237, and 176. In conclusion although the number of cases reported in the literature cited in the present review are rather small, it is clear that the DNA lesions occurring in the p53 gene in hematologic malignancies seem to fall in a similar pattern as those observed in other malignancies. Both the types of mutations and their distribution in the p53 protein structure agree with the general trend of mutations observed in malignancies of other tissues. Because most mutations seem to span the central part of the p53 protein, which was suggested to be involved in DNA binding, it is tempting to speculate that the mechanism by which p53 is inactivated is connected with conformational protein modification that affects the interactions of the p53 protein and the specific DNA targets. Development of the p53 field may advance two major aspects of cancer therapy in general. The first is associated with early diagnosis and prognosis of cancer patients and the second is related to the development of potential gene therapy that will restore the inactivated p53 in cancer cells. Elucidation of the biochemical and biologic functions of p53, along with the discovery of alterations in human cancer in epidemiologic studies, led to the development of functional screening tests to identify carriers of p53 germline mutations. Hopefully, the analysis of spectrum of p53 mutations will provide us with hypothesis regarding the environmental factors that contribute to development of human leukemia and lymphoma. Finally, the clinicians have included p53 in the arsenal of the clinical tools that enable detection of residual disease, establishing more accurate prognosis and remission.