Aberrant methylation during cervical carcinogenesis

Arvind K. Virmani, Carolyn Muller, Asha Rathi, Sabine Zoechbauer-Mueller, James Michael Mathis, Adi F. Gazdar

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Abstract

We studied the pattern of aberrant methylation during the multistage pathogenesis of cervical cancers. We analyzed a total of 73 patient samples and 10 cervical cancer cell lines. In addition, tissue samples [peripheral blood lymphocytes (n = 10) and buccal epithelial cells (n = 12)] were obtained from 22 healthy volunteers. On the basis of the results of preliminary analysis, the cervical samples were grouped into three categories: (a) nondysplasia/low-grade cervical intra-epithelial neoplasia (CIN; n = 37); (b) high-grade CIN (n = 17); and (c) invasive cancer (n = 19). The methylation status of six genes was determined (p16, RARβ, FHIT, GSTP1, MGMT, and hMLH1). Our main findings are as follows: (a) methylation was completely absent in control tissues; (b) the frequencies of methylation for all of the genes except hMLH1 were >20% in cervical cancers; (c) aberrant methylation commenced early during multistage pathogenesis and methylation of at least one gene was noted in 30% of the nondysplasia/low-grade CIN group; (d) an increasing trend for methylation was seen with increasing pathological change; (e) methylation of RARβ and GSTP1 were early events, p16 and MGMT methylation were intermediate events, and FHIT methylation was a late, tumor-associated event; and (f) methylation occurred independently of other risk factors including papillomavirus infection, smoking history, or hormone use. Although our findings need to be extended to a larger series, they suggest that the pattern of aberrant methylation in women with or without dysplasia may help identify subgroups at increased risk for histological progression or cancer development.

Original languageEnglish
Pages (from-to)584-589
Number of pages6
JournalClinical Cancer Research
Volume7
Issue number3
StatePublished - 1 Jan 2001

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Virmani, A. K., Muller, C., Rathi, A., Zoechbauer-Mueller, S., Mathis, J. M., & Gazdar, A. F. (2001). Aberrant methylation during cervical carcinogenesis. Clinical Cancer Research, 7(3), 584-589.