P53 MUTATIONS ASSOCIATED WITH BREAST, COLORECTAL, LIVER, LUNG, AND OVARIAN CANCERS

In this paper we describe a statistical analysis of the European Molec ular Library p53 mutation database comparing p53 mutations occurring i n breast, colorectal, liver, lung, and ovarian cancers. The analyses s how that mutation hot spots vary by cancer and that base pair changes and predicted amino acid changes in the gene product vary by cancer an d by codon. The analyses use relative frequencies and epidemiologic me asures of effect (prevalence ratios) not applied previously to these d ata. The five cancers in the database with the largest sample sizes we re breast (418), colorectal (398), liver (341), non-small cell lung (3 13), and ovarian cancers (251), for a total of 1,721 reports of p53 mu tations. The five cancers varied considerably in the distribution of m utations over sites, with different hot spots in each cancer. At the s ix most frequently reported codon sites, we compared base pair and ami no acid changes by type of cancer. The comparison of base pair of base pair changes indicated a predominance of particular base pair changes at a codon (for example, C-->T and G-->A changes at Codon 248) and th eir association with specific cancers (C-->T changes with colorectal c ancer and G-->A changes with both colorectal and breast cancers at cod on 248). Comparing predicted amino acid changes by codon and cancer wa s also intriguing as in codons 175 and 273, where arginine to cysteine and arginine to histidine changes were frequent in breast, colorectal , and ovarian cancers. Variations in p53 mutational distributions by m ay be explained by different exposures to carcinogens or by organ-spec ific clonal selection. Further research may be stimulated by this anal ysis.