P53 GENE-MUTATIONS INSIDE AND OUTSIDE OF EXONS-5-8 - THE PATTERNS DIFFER IN BREAST AND OTHER CANCERS

Most studies of mutations in the p53 tumor suppressor gene in tumors h ave examined only exons 5-8. Our laboratory previously round 64 mutati ons in exons 5-8 of the p53 gene in 194 primary breast cancers. Herein , we report 18 additional mutations found outside of exons 5-8. Mutati ons are present in exons 4, 9 and 10, and flanking splice junctions, b ut not in the promotor region or in exons 1, 2, 3 and 11. No missense mutations are found outside of exons 5-8, is predominance of frameshif t mutations lesser numbers of nonsense and splice site mutations. In c ontrast, the majority of mutations in exons 5-8 in this sample are mis sense changes and all of these are at amino acids that are identical i n the 11 known p53 sequences that represent about 1.6 billion years of evolutionary divergence. The difference in mutational pattern between these two regions of the p53 gene is due to a lack of missense mutati ons and inframe microdeletions outside of exons 5-8, A review of our d atabase of p53 mutations (De Vries et al., in preparation) shows that the patterns of mutation inside and outside of exons 5-8 differ in oth er types of cancers as well. The paucity of missense mutations in exon s 2-4 and 9-11 in breast and other cancers (even at amino acids identi cal throughout p53 gene evolution) suggest that at least some missense mutations result in a phenotype other than malignant transformation. These data also illustrate the importance of examining identical exons when comparing the pattern of p53 gene mutations in different populat ions.