Evaluation of candidate methylation markers to detect cervical neoplasia

Hamon Center for Therapeutic Oncology Research, Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75930, USA.
Gynecologic Oncology (Impact Factor: 3.77). 01/2008; 107(3):549-53. DOI: 10.1016/j.ygyno.2007.08.057
Source: PubMed


Studies of cervical cancer and its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3), have identified genes that often show aberrant DNA methylation and therefore represent candidate early detection markers. We used quantitative PCR assays to evaluate methylation in five candidate genes (TNFRSF10C, DAPK1, SOCS3, HS3ST2 and CDH1) previously demonstrated as methylated in cervical cancer.
In this analysis, we performed methylation assays for the five candidate genes in 45 invasive cervical cancers, 12 histologically normal cervical specimens, and 23 liquid-based cervical cytology specimens confirmed by expert review as unequivocal demonstrating cytologic high-grade squamous intraepithelial lesions, thus representing the counterparts of histologic CIN3.
We found hypermethylation of HS3ST2 in 93% of cancer tissues and 70% of cytology specimens interpreted as CIN3; hypermethylation of CDH1 was found in 89% of cancers and 26% of CIN3 cytology specimens. Methylation of either HS3ST2 or CDH1 was observed in 100% of cervical cancer tissues and 83% of CIN3 cytology specimens. None of the five genes showed detectable methylation in normal cervical tissues.
Our data support further evaluation of HS3ST2 and CDH1 methylation as potential markers of cervical cancer and its precursor lesions.

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    • "with the random effects model (Fig 1), which showed that DAPK1 promoter methylation is associated with cervical cancer and therefore, that it might play an important role in the pathogenesis of cervical cancer. This result was consistent with the findings of previous studies [11], [20]. However, significant heterogeneity was observed in those 15 studies, and the reason for heterogeneity could not be explained at the beginning. "
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    ABSTRACT: Background Death-associated protein kinase1 (DAPK1) is an important tumor suppressor gene. DNA methylation can inactivate genes, which has often been observed in the carcinogenesis of cervical cancer. During the past several decades, many studies have explored the association between DAPK1 promoter methylation and cervical cancer. However, many studies were limited by the small samples size and the findings were inconsistent among them. Thus, we conducted a meta-analysis to assess the association between DAPK1 promoter methylation and cervical cancer. Methods We systematically searched eligible studies in the PubMed, Web of Science, EMBASE and CNKI databases. Using meta-regression, subgroup analysis and sensitivity analysis, we explored the potential sources of heterogeneity. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated by Meta-Analysis in R. Results A total of 15 studies from 2001 to 2012, comprising 818 tumor tissues samples and 671 normal tissues samples, were analyzed in this meta-analysis. The frequencies of DAPK1 promoter methylation ranged from 30.0% to 78.6% (median, 59.3%) in cervical cancer tissue and 0.0% to 46.7% (median, 7.8%) in normal cervical tissue. The pooled OR was 19.66 (95%CI = 8.72–44.31) with the random effects model, and heterogeneity was found through the sensitivity analysis. The I2 = 60% (P = 0.002) decreased to I2 = 29.2% (P = 0.144) when one heterogeneous study was excluded, and the pooled OR increased to 21.80 (95%CI = 13.44–35.36) with the fixed effects model. Conclusion The results suggested a strong association between DAPK1 promoter methylation and cervical cancer. This study also indicated that DAPK1 promoter methylation may be a biomarker during cervical carcinogenesis that might serve as an early indication of cervical cancer.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "E-cadherin gene hypermethylation occurs according to the severity of cervical dysplasia. Shivapurkar et al.[35] found this epigenetic change in 89% of invasive cervical cancers whereas only in 26% of CIN III cases and none of normal tissues. Thus, E-cadherin gene hypermethylation might be a candidate epigenetic marker for early detection of cervical cancer. "
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    ABSTRACT: Persistent infection with high-risk types of human papillomavirus (HPV) is known to cause cervical cancer; however, additional genetic and epigenetic alterations are required for progression from precancerous disease to invasive cancer. DNA methylation is one of the earliest and most frequent molecular alterations in cervical carcinogenesis. In this review, we summarize DNA methylation within the human papillomavirus genome and human genome and identify its clinical implications. Methylation of the HPV long control region (LCR) and L1 gene is common during cervical carcinogenesis and increases with the severity of the cervical neoplasm. The L1 gene of HPV16 and HPV18 is consistently hypermethylated in invasive cervical cancers and can potentially be used as a clinical marker of cancer progression. Moreover, promoters of tumor suppressor genes (TSGs) involved in many cellular pathways are methylated in cervical precursors and invasive cancers. Some are associated with squamous cell carcinomas, and others are associated with adenocarcinomas. Identification of methylated TSGs in Pap smear could be an adjuvant test in cervical cancer screening for triage of women with high-risk HPV, atypical squamous cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesion (LSIL). However, consistent panels must be validated for this approach to be translated to the clinic. Furthermore, reversion of methylated TSGs using demethylating drugs may be an alternative anticancer treatment, but demethylating agents without toxic carcinogenic and mutagenic properties must be identified and validated.
    Full-text · Article · Aug 2012 · Chinese journal of cancer
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    • "In some tumor types, including cervical carcinomas, Ecadherin may be transcriptionally silenced by DNA hypermethylation (Chen et al., 2003; Dong et al., 2001; Kang et al., 2005; Narayan et al., 2003; Shivapurkar et al., 2007; Terra et al., 2007; Yang et al., 2006). While the mechanism of the decreased E-cadherin expression in HPV oncoprotein expressing HFKs is not clear, our results are consistent with a recent report that depletion of HPV16 E7 by siRNA in HPV16 transformed human keratinocytes restored normal E-cadherin expression through a mechanism that is likely independent of the transcription factors slug and snail (Caberg et al., 2008). "
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    ABSTRACT: Cancer-associated epithelial to mesenchymal transition (EMT) is crucial for invasion and metastasis. Molecular hallmarks of EMT include down-regulation of the epithelial adhesion protein E-cadherin and de-novo expression of N-cadherin and the mesenchymal intermediate filament proteins vimentin and fibronectin. Expression of HPV16 E7 in normal human epithelial cells caused increased levels of vimentin and fibronectin, whereas the epithelial adhesion protein E-cadherin was expressed at decreased levels. Similar expression patterns of vimentin, fibronectin and E-cadherin were also detected in cells expressing HPV16 E6 and E7 or the entire HPV16 early transcriptional unit. HPV16 E6 and E7 were each able to induce N-cadherin expression. Interestingly, these changes in expression levels of EMT-associated proteins are not similarly reflected at the level of mRNA expression, suggesting that HPV16 oncoproteins also modulate EMT through non-transcriptional mechanisms. Hence, HPV16 oncoproteins may contribute to malignant progression through EMT induction.
    Full-text · Article · Jul 2009 · Virology
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