POOLED ANALYSIS OF P53 MUTATIONS IN HEMATOLOGICAL MALIGNANCIES

A computerized database is described that contains information about 5 07 mutations in the p53 gene of hematologic tumors and corresponding c ell lines. Analysis of these mutations indicated the following finding s: First, mutational spectrum analysis in these tumors was found to be similar to the pattern found for other solid tumors. However when the patterns of base substitutions were examined separately according to the types of hematologic malignancies, followed by subgroup analysis, notable differences (in some cases of statistical significance) emerge d. Second, mutational pattern analysis indicates that about 48% of bas e substitutions in hematologic tumors are suspected to be associated w ith carcinogen exposure. Third, deletions and insertions are localized mainly to exons 5-8 and repeated DNA sequences. However, the unusual profile of variations in frequency within each type of tumor suggests that, in addition to endogenous damage to template DNA, there is the f actor of exposure to environ mental physical and chemical carcinogens/ mutagens. Fourth, p53 protein alterations analysis indicate that most of the changes in the amino acids are ''semiconservative,'' presumably in order to avoid disrupting the structure of the p53 monomer. Consis tent with this notion, structural mutations are more conservative than the binding mutations. Finally, molecular mechanisms that lead to p53 mutations, etiological factors that play a role in their formation, a nd the pathophysiological significance of consequent p53 protein alter ations are discussed. (C) 1998 Wiley-Liss, Inc.