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Howard Hughes Medical Institute and Departments of Internal Medicine and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109 [A. P. F.]; Department of Biochemistry, University of Missouri, Columbia, Missouri 65211 [C. W. G., K. C. K.]; and Department of Biochemistry, Tulane University School of Medicine, New Orleans, Louisiana 70112 [M. E.]
DNA methylation appears to play an important role in both physiological and experimentally modified gene expression, and alterations in DNA methylation have been described in animal tumor models and in transformed cells and tumor cell lines. However, there have been comparatively few reports on DNA methylation in primary human malignancies, and these reports are somewhat contradictory. While individual genes have shown hypomethylation in colon cancer and premalignant adenomas as well as in lung cancer, other genes have shown increased methylation, and absolute measures of 5-methylcytosine content have shown decreases in malignancies but not in premalignant adenomas. We have used a sensitive quantitative measurement of 5-methylcytosine content by high performance liquid chromatography revealing an unequivocal hypomethylation of tumor DNA. An average of 8 and 10% reduction in genomic 5-methylcytosine content was seen in apparently all colon adenomas and adenocarcinomas, respectively, and there was no significant difference between benign and malignant tumors. This is a substantial quantitative alteration and suggests a pervasive abnormality in the control of DNA methylation. Surprisingly, three patients with the highest 5-methylcytosine content in their normal colon appear to have a germline predisposition to cancer (Lynch syndrome).
1 This work was supported in part by the Howard Hughes Medical Institute and grants from the National Foundation/March of Dimes and the Higher Education Research Assistance Act of the State of Missouri.
2 To whom requests for reprints should be addressed.
Received 8/11/87. Revised 11/30/87. Accepted 12/ 4/87.
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