Analysis of Aberrant DNA Methylation and Human Papillomavirus DNA in Cervicovaginal Specimens to Detect Invasive Cervical Cancer and Its Precursors

Widschwendter, Andreas; Gattringer, C.; Ivarsson, Lennart; Fiegl, Heidi; Schneitter, Alois; Ramoni, A; Müller, Hannes M.; Wiedemair, Annemarie; Jerabek, Susanne; Müller‐Holzner, Elisabeth; Goebel, Georg; Marth, Christian; Widschwendter, Martin

doi:10.1158/1078-0432.ccr-03-0143

Cited by 62 publications

(47 citation statements)

References 20 publications

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“…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%

“…Decrease or loss of E-cadherin expression is a common feature of many human epithelial cancers, including cervical cancer, although a decreased expression of this molecule has been described in metastasis, but not primary tumors (42). Promoter hypermethylation has been proposed as an explanation for the decrease of E-cadherin expression (24,43) and was even suggested as a potential marker for identifying cervical cancer patients at high risk for relapse (32).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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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“…The literature on hypermethylated genes in cervical cancer is limited and even further limited in precancerous lesions. The genes of choice in this study were those for which there was evidence of a role for hypermethylation for progression of cervical intraepithelial neoplasia to cervical cancer (4,5,29,32). A nested two-step methyl-specific PCR was carried out on the bisulphite-treated DNA as previously described (33).…”

Section: Methodsmentioning

confidence: 99%

“…Although it is difficult to establish whether such epigenetic alterations are causative or consequential of cancer, there is evidence that they can occur early in the neoplastic process (3). There have been studies to explore the promoter methylation status of selected tumor suppressor genes in cases of cervical cancer and precancerous lesions (4)(5)(6). In general, however, these studies did not have sufficient power to detect differences in individual genes.…”

Section: Introductionmentioning

confidence: 99%

Folate Status and Aberrant DNA Methylation Are Associated With HPV Infection and Cervical Pathogenesis

Flatley

McNeir

Balasubramani

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Aberrant DNA methylation is a recognized feature of human cancers, and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also suggest that folate status is associated with the natural history of human papillomavirus (HPV) infection. A cross-sectional study was conducted to test the hypothesis that folate status and aberrant DNA methylation show a progressive change across stages of cervical pathology from normal cells to cervical cancer. Additionally, we postulated that a genespecific hypermethylation profile might be used as a predictive biomarker of cervical cancer risk. DNA hypermethylation of seven tumor suppressor genes, global DNA hypomethylation, systemic folate status, and HPV status were measured in 308 women with a diagnosis of normal cervix (n = 58), low-grade cervical intraepithelial neoplasia (CIN1; n = 68), high-grade cervical intraepithelial neoplasia (CIN2, n = 56; and CIN3, n = 76), or invasive cervical cancer (ICC; n = 50). Lower folate status was associated with high-risk HPV infection (P = 0.031) and with a diagnosis of cervical intraepithelial neoplasia or invasive cervical cancer (P < 0.05). Global DNA hypomethylation was greater in women with invasive cervical cancer than all other groups (P < 0.05). A cluster of three tumor suppressor genes, CDH1, DAPK, and HIC1, displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (P < 0.05). These findings are compatible with a role for folate in modulating the risk of cervical cancer, possibly through an influence over high-risk HPV infection. DAPK, CDH1, and HIC1 genes are potential biomarkers of cervical cancer risk.

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“…Several studies have reported the hypermethylation of many genes, including DAPK1, RARB, and TIMP3 in high-grade CINs and/or cervical cancer, which strongly suggest that DNA methylation could be used as a possible biomarker for the early diagnosis for cervical cancer. 7,8,16 Recent studies have also shown that the combination of a primary hrHPV DNA test with a gene methylation panel composed of JAM3, EPB41L3, TERT, and C13ORF18 to triage patients resulted in an increase in the identification of CIN31 and a higher percentage of correct referrals compared with the use of an hrHPV DNA test in combination with the Pap smear. 18 In this study, we showed that the methylation status of SIM1 can distinguish cervical cancer cells from normal cells, CIN1, or CIN2 using cervical brush specimens ( Figure 1D and Table 2).…”

Section: Discussionmentioning

confidence: 99%

Aberrant single‐minded homolog 1 methylation as a potential biomarker for cervical cancer

Kim

Jin

et al. 2017

Diagnostic Cytopathology

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BackgroundThe aim of this study is to evaluate the possibility of using the methylation status of single‐minded homolog 1 (SIM1) as a diagnostic biomarker for cervical cancer.MethodsAll the patient and normal specimens including the normal cervix (n = 10), cervical cancer tissues (n = 45), blood (n = 45), and cervical brush specimens (n = 110) were retrospectively obtained. Quantitative methylation‐specific PCR was performed to detect SIM1 methylation in primary tumors, cervical brush specimens, and plasma circulating cell‐free DNA (ccfDNA). SIM1 expression was detected by western blot analysis.ResultsWe found that SIM1 was highly methylated in the majority of the cervical cancer tissues that we tested, but not in any of the normal tissues. Hypermethylation of SIM1 led to a pronounced reduction in SIM1 expression in cervical cancer tissues compared with normal cervix. SIM1 methylation status on cervical brush specimens also distinguished cervical cancer from normal, cervical intraepithelial neoplasia (CIN) 1 and 2. The degree of SIM1 methylation was significantly associated with the severity of the disease (Ptrend < .0001). We also investigated the possibility of detecting methylated SIM1 in plasma ccfDNA from cervical cancer patients. Methylated SIM1 was detected in 36.6% (15/41) of ccfDNA samples, and concordance rate with the matched cancer tissues was 41.5% (17/41) with sensitivity 38.5% and specificity 100%.ConclusionThis study has shown that SIM1 is frequently hypermethylated in cervical cancer, compared with normal cervix tissue, CIN1 and 2 samples, suggesting that the methylation status of SIM1 could be a potential diagnostic biomarker for cervical cancer.

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Analysis of Aberrant DNA Methylation and Human Papillomavirus DNA in Cervicovaginal Specimens to Detect Invasive Cervical Cancer and Its Precursors

Cited by 62 publications

References 20 publications

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

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

Folate Status and Aberrant DNA Methylation Are Associated With HPV Infection and Cervical Pathogenesis

Aberrant single‐minded homolog 1 methylation as a potential biomarker for cervical cancer

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