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Background  High risk type human papilloma viruses (HR-HPV) induce carcinomas of the uterine cervix by expressing viral oncogenes E6 and E7. Oncogene E7 of HR-HPV disrupts the pRb/E2F interaction, which negatively regulates the S phase entry. Expression of tumor suppressor p16 ink4a  drastically increases in majority of HR-HPV associated carcinomas due to removal of pRb repression. The p16 ink4a  overexpression is an indicator of an aberrant expression of viral oncogenes and may serve as a marker for early diagnostic of cervical cancer. On the other hand, in 25–57% of cervical carcinomas hypermethylation of the  p16 INK4a  promoter has been demonstrated using a methylation-specific PCR, MSP. To evaluate a potential usage of the  p16 INK4a  5' CpG island hypermethylation as an indicator of tumor cell along with p16 ink4a  overexpression, we analyzed the methylation status of  p16 INK4a  in cervical carcinomas    Methods  Methylation status of  p16 INK4a  was analyzed by MSP and by bisulfite-modified DNA sequencing. The expression of p16 ink4a  was analyzed by RT-PCR and by immunohistochemical technique.    Results  The extensive methylation within  p16 INK4a  5' CpG island was not detected either in 13 primary cervical carcinomas or in 5 cancer cell lines by bisulfite-modified DNA sequencing (including those that were positive by MSP in our hands). The number and distribution of rare partially methylated CpG sites did not differ considerably in tumors and adjacent normal tissues. The levels of the  p16 INK4a  mRNA were increased in carcinomas compared to the normal tissues independently of the number of partially methylated CpGs within 5'CpG island. The transcriptional activation of  p16 INK4a  was accompanied by p16 ink4a  cytoplasmic immunoreactivity in the majority of tumor cells and presence of a varied number of the p16 positive nuclei in different tumors.    Conclusion  Hypermethylaion of the  p16INK4a  5' CpG island is not a frequent event in HR-HPV-positive cervical carcinomas and cannot be an effective marker of cancer cells with up-regulated expression of p16 ink4a . Our data confirm other previous studies claiming specific  p16INK4a  up-regulation in the majority of cervical carcinomas at both the protein and mRNA levels. Cytoplasmic accumulation of p16 ink4a  is a feature of cervical carcinomas.

Up-regulation of expression and lack of 5' CpG island hypermethylation of p16 INK4ain HPV-positive cervical carcinomas