Association between malignant progression of colorectal adenomas and DNA replication error and inhibition of apoptosis

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The aim of this study is to investigate the association between malignant potency of colorectal adenomas to progress to carcinoma and the inhibition of apoptosis and DNA replication errors in colorectal adenomas. We examined p53 and bcl-2 overexpression, and analyzed dinucleotide instability in colorectal adenomas showing various degree of dysplasia and carcinomas invading submucosa. Overexpression of p53 was associated with progression dysplasia and depth of cancer invasion. However, the frequency of bcl-2 overexpression was not increased according to the degree of dysplasia. We also studied p21 WAF1 and PCNA expression in adenomas with various degree of dysplasia and carcinomas with submucosal invasion, and investigated whether the irregularity of cell cycle was related to the development of colorectal tumors. In adenomas showing high grade dysplasia, the PCNA labeling index in adenomas which were positive for p21 WAF1 and negative for p53 overexpression was significantly lower than in adenomas which were both positive for p21 WAF1 and p53 overexpression. These results suggest that proliferation of some of adenomas with high grade dysplasia might be suppressed by p21 WAF1 expression which was induced irrespective of p53 expression. The analysis of genetic alterations in carcinomas showed that 27% of 87 tumors had DNA replication error. We undertook analysis of DNA replication error in DNAs from formalin-fixed paraffin-embedded adenomas, but efficiency of PCR amplification of such DNAs was not so good to perform the study. Further study is necessary to clarify the role of DNA replication error in colorectal carcinogenesis.