The patterns of p53 gene mutations differ inside and outside of exons 5-8 in breast and other cancers

Most studies of the p53 gene in tumors examine only exons 5-8. In these exons, there is a predominance of missense mutations clustered in four regions of high evolutionary conservation. We previously found 64 mutations in exons 5-8 of the p53 gene in 194 primary breast cancers. Herein, we report 18 additional mutations found by analyzing the promotor region, the first noncoding exon, and the remaining coding exons. Mutations were found in exons 4, 9, and 10, and flanking splice junctions, but not in the promotor region or in exons 1, 2, 3, and 11. Outside of exons 5-8 not a single missense mutation was found. Microdeletions and microinsertions predominate but nonsense and splice site mutations also occur. In contrast, the majority of mutations in exons 5-8 were missense changes which exclusively occurred at amino acids that were identical in all known p53 sequences which represent about 1.6 billion years of evolutionary divergence. The difference in the mutational pattern between these two regions of the p53 gene is due to a lack of missense and inframe microdeletion mutations outside exons 5-8 (p<.0001), whereas frameshift deletions and insertions, nonsense mutations and splicing defects are equally distributed over the gene. A reviewmore » of the literature shows that the difference in the patterns of mutation inside and outside of exons 5-8 we have found in breast cancer is present in other types of cancers as well. These data show the importance of comparing equivalent exons when examining the pattern of p53 gene mutation in different populations. In addition, the paucity of missense mutations in breast and other cancers (even at amino acids identical throughout p53 gene evolution) indicates that at least some of the missense mutations in exons 2-4 and 9-11 result in a phenotype other than malignant transformation.« less