Aberrant methylation during cervical carcinogenesis.
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 intraepithelial 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, RARbeta, 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 RARbeta 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.
Virmani
A K
AK
Hamon Center for Therapeutic Oncology Research, and Department of Pathology, University of Texas Southwestern Medical Center, Dallas 85930, USA.
Muller
C
C
Rathi
A
A
Zoechbauer-Mueller
S
S
Mathis
M
M
Gazdar
A F
AF
D017766:Acid Anhydride Hydrolases; D002584:Cervix Uteri / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D019942:Genes, p16 / Q000235:genetics; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008745:Methylation; D009363:Neoplasm Proteins; D011506:Proteins / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D009363:Neoplasm Proteins; D011506:Proteins; D018168:Receptors, Retinoic Acid; D000099170:Bis(5'-adenosyl)triphosphatase; C082925:retinoic acid receptor beta; C496556:GSTP1 protein, human