Analysis of gene alterations in the premalignant lesion of colorectum

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The recent advance in molecular biology revealed that a number of cancer-associated genes play an important role in multistep carcinogenesis in colorectum. However, many of the reports are based on the analysis on a series of colorectal adenoma or carcinoma tissues, and little is known about the timing of the occurence or the precise role of the gene alteration in cach individual case. Carcinoma in adenoma which we used in the present study is the very initial malignancy in adenoma-carcinoma sequence in colon and is thought to be an ideal clinical material for the study of the gene alteration associated with malignant transformation. In addition, microanalysis which we employed enabled us to analyze DNA of both normal cpithelium, adenoma with the different grade of atypia and the carcinoma in each case with the minimal contamination. We are able to compare the result of DNA analysis to the pathological findings including immunohistochemistry, therefore, genetic analysis of histopatholo … More gical level can be done. The result of our present study clearly show that the p53 gene alteration plays a key role in the turning point of malignant conversion from adenoma to carcinoma. Therefore, analysis of p53 gene alteration should be useful also in the clinical application. On the contrary, K-ras gene mutation was shown to be associated with the grade of atypia of adenoma in accordance with the previous reports. There is no difference in the mutation rate of K-ras in between adenoma and carcinoma in adenoma, showing no evidence of the participation of K-ras in malignant transformation. The analysis of K-ras in the multple lesions with the different grade of atypia suggested that K-ras mutaion is merely the consequence of the development of dysplasia. We also did the analysis of genomic instability derived from the abnormality in DNA mismatch repair system and the cell cycle regulator such as WAF1, cyclin D,cdc2/cdk2 in colorectal tumor, and obtained some preliminary results. Some of these result have been already published in the paper as described in this report. Less