DNA Methylation in Serum and Tumors of Cervical Cancer Patients

Widschwendter, Andreas; Müller, Hannes M.; Fiegl, Heidi; Ivarsson, Lennart; Wiedemair, Annemarie; Müller‐Holzner, Elisabeth; Goebel, Georg; Marth, Christian; Widschwendter, Martin

doi:10.1158/1078-0432.ccr-0825-03

Cited by 119 publications

(71 citation statements)

References 18 publications

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“…hTERT gene plays a critical role in cell division and serves as a mitotic clock for cell proliferation (17). In our study we found that the mean levels of hTERT promoter methylation were increased with increasing cytological and histological severity in agreement with previous relative reports and also that QMSP hTERT methylation values could distinguish normal from premalignant and cancer tissues, as well as premalignant from cancer cervical tissues (25,37).…”

Section: Discussionsupporting

confidence: 92%

“…Research in the last few years clearly proved that epigenetic events and particularly methylation are involved in cancer initiation and progression and that their expression profiling can be exploited for the classification, diagnosis and prediction of human malignancies (25)(26)(27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

“…The primers and probes that were used for the MethyLight reactions have been previously described (25)(26)(27) and are shown in Table II …”

Section: Real-time Methylight Analysismentioning

confidence: 99%

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Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression

Iliopoulos

Oikonomou²,

Messinis³

et al. 2009

Oncol Rep

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Abstract. DNA hypermethylation occurs during the multistep process of cervical carcinogenesis. We investigated whether the methylation status in the promoter region of a potential oncogene, the human telomerase reverse transcriptase (hTERT), and the tumor suppressor genes deathassociated protein kinase (DAPK) and O 6 -methylguanine DNA methyltransferase (MGMT), were able to distinguish the early from late stages of cervical oncogenesis. The methylation status in the promoter of these genes was analyzed using real-time MethyLight analysis in 115 cervical specimens, including normal, premalignant [atypical squamous epithelial cells (ASCUS), low-grade squamous intraepithelial lesions (LGSIL), high-grade squamous intraepithelial lesions (HGSIL)] and cancer specimens. Clinicopathological parameters (cytology, histology, grade, stage) were compared to the levels of pro-moter hypermethylation. We found that hTERT, MGMT and DAPK hypermethylation levels were increased during cervical oncogenesis progression. hTERT promoter hypermethylation was able to distinguish normal from cancer (p=0.008), normal from premalignant (p=0.036), as well as premalignant from cervical cancer cases (p=0.003). A significant association was also observed between all three genes and the grade of cervical cancer, with hTERT showing a better association (p<0.0001). Our data suggest that the combination of hTERT, MGMT, DAPK promoter hypermethylation could have a potential function as molecular biomarker of cervical oncogenesis progression.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression

Iliopoulos

Oikonomou²,

Messinis³

et al. 2009

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…Hypermethylation of CpG islands of promoter genes has been identified and associated with loss of expression of many potential key genes in cancer cells (8). Several studies have investigated the methylation status of genes in cervical cancer and evaluated their implication in carcinogenesis (17,18,(28)(29)(30)(31)(32)(33)(34)(35). In the present study we have investigated the methylation status of p16 INK4a and E cadherin gene promoters in four cervical cell lines, 20 normal HPV negative cervical swabs, and 22 cervical cancer specimens from Moroccan women.…”

Section: Discussionmentioning

confidence: 96%

Status of p16<SUP>INK4a</SUP> and E-Cadherin Gene Promoter Methylation in Moroccan Patients With Cervical Carcinoma

Attaleb¹,

W²,

Khyatti³

et al. 2009

oncol res

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Aberrant methylation of tumor suppressor gene promoters has been extensively investigated in cervical cancer. Transcriptional silencing, as a main consequence of hypermethylation of CpG islands, is the predominant mechanism of p16 INK4a and E-cadherin gene inactivation in malignant epithelial tumors. This study was conducted to evaluate the promoter methylation status of p16 INK4a and E-cadherin genes in 22 specimens of cervical carcinomas, four cervical cancer cell lines (HeLa, SiHa, Caski, C33A), and 20 human papillomavirus negative specimens, obtained from normal cervical swabs, using the methylation-specific PCR approach. Hypermethylation of the 5′ CpG island of the p16 INK4a and E-cadherin genes were found in 13 (59.1%) and 10 (45.5%) of 22 cervical cancer samples, respectively. Furthermore, our findings did not show any correlation between promoter methylation of p16 INK4a and E-cadherin genes and clinicopathological parameters, including HPV infection, phenotypic distribution, and stage of the disease. However, hypermethylation of E-cadherin gene promoter appears to be age related in cervical cancer, whereas the frequency of aberrant methylation of p16 INK4a gene promoter is unchanged according to the age of patients. Thus, caution must be made to use these markers in the diagnosis of cervical cancer. However, dietary or pharmaceutical agents that can inhibit these epigenetic events may prevent or delay the development of cervical cancer.

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“…In several of these studies, methylation of up to 16 gene promoters has been tested on cervical cancer biopsies, showing that up to 93% of them were positive for at least one of the methylation markers tested (Dong et al, 2001;Virmani et al, 2001;Narayan et al, 2003;Gustafson et al, 2004;Widschwendter et al, 2004;Feng et al, 2005;Zambrano et al, 2005;Wisman et al, 2006). However, for most of the genes studied, it is still unclear to what extent and at what stage promoter methylation reflects a functionally important step in the transformation process.…”

mentioning

confidence: 99%

Sequential gene promoter methylation during HPV-induced cervical carcinogenesis

et al. 2007

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We aimed to link DNA methylation events occurring in cervical carcinomas to distinct stages of HPV-induced transformation. Methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) analysis of cervical carcinomas revealed promoter methylation of 12 out of 29 tumour suppressor genes analysed, with MGMT being most frequently methylated (92%). Subsequently, consecutive stages of HPV16/18-transfected keratinocytes (n ¼ 11), ranging from pre-immortal to anchorage-independent phenotypes, were analysed by MS-MLPA. Whereas no methylation was evident in pre-immortal cells, progression to anchorage independence was associated with an accumulation of frequent methylation events involving five genes, all of which were also methylated in cervical carcinomas. TP73 and ESR1 methylation became manifest in early immortal cells followed by RARb and DAPK1 methylation in late immortal passages. Complementary methylation of MGMT was related to anchorage independence. Analysis of nine cervical cancer cell lines, representing the tumorigenic phenotype, revealed in addition to these five genes frequent methylation of CADM1, CDH13 and CHFR. In conclusion, eight recurrent methylation events in cervical carcinomas could be assigned to different stages of HPV-induced transformation. Hence, our in vitro model system provides a valuable tool to further functionally address the epigenetic alterations that are common in cervical carcinomas.

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DNA Methylation in Serum and Tumors of Cervical Cancer Patients

Cited by 119 publications

References 18 publications

Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression

Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression

Status of p16<SUP>INK4a</SUP> and E-Cadherin Gene Promoter Methylation in Moroccan Patients With Cervical Carcinoma

Sequential gene promoter methylation during HPV-induced cervical carcinogenesis

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