GLOBAL DNA HYPOMETHYLATION INCREASES PROGRESSIVELY IN CERVICAL DYSPLASIA AND CARCINOMA

Background. Global DNA hypomethylation has been observed in some human neoplasms and has been implicated as an important factor in carcinoge nesis. The current study was designed to assess whether DNA hypomethyl ation occurs in cervical dysplasia and cancer, and to determine the re lationship between the degree of DNA hypomethylation and the grade of neoplasia. Methods. Cervical biopsy specimens were obtained from colpo scopically identifiable lesions in 41 patients with abnormal Pap smear results. The extent of global DNA methylation was assessed by incubat ing the extracted DNA with [H-3]-S-adenosylmethionine and Sss1 methylt ransferase, an enzyme that specifically catalyzes the transfer of meth yl groups to cytosine residues in the cytosine-guanine doubler. The de gree of exogenous H-3-methyl group incorporation into the DNA therefor e is related reciprocally to the extent of endogenous DNA methylation. These data were compared with the histopathologic classification of t he lesions. Results. The extent of H-3-methyl group incorporation was increased threefold and sevenfold in the DNA from cervical dysplasia a nd cancer, respectively, compared with the DNA from normal cervical ti ssue (P = 0.006, analysis of variance). Significant incremental increa ses in DNA hypomethylation were observed in the progression from norma l and low grade squamous intraepithelial lesions (SIL) to high grade S IL and to cancer (P < 0.0001,trend). Conclusions. These data show that global DNA hypomethylation is a significant epigenetic event in cervi cal carcinogenesis and that the degree of DNA hypomethylation increase s with the grade of cervical neoplasia. These data suggest that global DNA methylation may serve as a biochemical marker of cervical neoplas ia.