Implications of p53 mutation spectrum for cancer etiology in gastric cancers of various histologic types from a high-risk area of central Italy

Examination of p53 mutation spectra may provide clues to molecular mechanis ms involved in different histologic types of gastric cancer. A total of 105 gastric cancer cases classified according to the Lauren's system were sele cted from a high-risk area around Florence, Italy. Exons 5-8 of the p53 gen e were examined for mutations by the polymerase chain reaction-single stran d conformation polymorphism technique and DNA sequencing, using DNA from fo rmalin-fixed paraffin-embedded tissues. Mutation frequency was similar in i ntestinal-type (12/28) and unclassified tumors (9/18), but was significantl y lower in diffuse cancers (12/57, P < 0.05), A similar frequency of p53 mu tations was observed among tumor stages in both intestinal-type and unclass ified cancers, but in diffuse tumors mutations tended to be associated with invasion beyond the muscularis propria, When base changes were considered, G:C-->A:T transitions at CpG sites were the most common mutations for all the three tumor types with 6 of 11 (55%) in intestinal type, 8 of 12 (67%) in diffuse type, and 5 of 8 (63%) in unclassified tumors. Frequent p53 muta tions in both intestinal-type and unclassified tumors support the hypothesi s that unclassified tumors represent variants of the intestinal type and su ggest that unclassified tumors, like the intestinal type, may also associat e with environmental exposures. The predominance of G:C-->A:T transitions a t CpG sites, which are associated with methyltransferase-induced DNA methyl ation at carbon 5 of cytosine, in all three tumor types suggests that the s tatus of DNA methylation may be the major determinant for p53 mutations and may be also equally important in gastric carcinogenesis regardless of hist ology.