DNA methylation abnormalities, including widespread hypomethylation and regional areas of hypermethylation, are a consistent molecular feature of human neoplastic cells. These changes, particularly hypermethylation, potentially alter chromatin structure and could be major factor in the accrual of genetic instability events which drive tumor progression. The hypermethylation may result from abnormal expression of the DNA-methyl transferase (DNA-MT) gene. We have cloned a portion of the human DNA-MT gene and find that its expression is dramatically increased, at the steady- state transcript level, in established lines of multiple types of human cancer cells. DNA-MT gene expression is coupled to DNA synthesis, and rises sharply during DNA replication prior to cell division. The present proposal will evaluate DNA-MT gene expression as a marker for the earliest events in the evolution of human colon cancer. Our initial studies reveal exponential increases in DNA-MT transcript levels for each stage of colon cancer progression, including increased levels in histologically normal appearing colonic mucosa distant from pre-malignant adenomatous polyps and cancers. We will determine, using PCR and cytochemical techniques, whether sequential increases in DNA MT transcript levels can: (a) define genetic predisposition states to colon cancer developments including those underlying the common forms of colon cancer; (b) define prognostic parameters for progression of pre-malignant adenomatous polyps and prediction of colon cancer metastatic potential; and (c) identify the cellular changes underlying evolution of colon cancer in a rodent carcinogenesis model. Positive findings in the above studies may lead, in future work, to similar evaluation of other major cancers including bladder, prostate, cervical, breast and lung.
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