Methylated Host Cell Gene Promoters and Human Papillomavirus Type 16 and 18 Predicting Cervical Lesions and Cancer

Liu

Chinese Medical Journal

et al. 2018

Background:Promoter methylation of MGMT and C13ORF18 has been confirmed as a potential biomarker for early diagnosis of cervical cancer. The aim of this study was to evaluate the performance of MGMT and C13ORF18 promoter methylation for triage of cytology screening samples and explore the potential mechanism.Methods:Methylation-sensitive high-resolution melting was used to detect promoter methylation of MGMT and C13ORF18 in 124 cervical samples. High-risk human papillomavirus (HR-HPV) was detected by the Digene Hybrid Capture 2®. Gene methylation frequencies in relation to cervical intraepithelial neoplasia (CIN) were analyzed. Frequencies were compared by Chi-square tests. The expression of gene biomarkers and methylation regulators was analyzed by immunohistochemical staining, real-time fluorescence quantitative polymerase chain reaction, and Western blot.Results:For triage of low-grade squamous intraepithelial lesion (LSIL), gene methylation increased specificity from 4.0% of HR-HPV detection to 30.8% of MGMT (χ2 = 9.873, P = 0.002) and to 50.0% of C13ORF18 (χ2 = 21.814, P = 0.001). For triage of atypical squamous cells of undetermined significance, HR-HPV detection had higher positive predictive value of 54.8%. Either MGMT or C13ORF18 methylation combined with HR-HPV increased the negative predictive value to 100.0% (χ2 = 9.757, P = 0.002). There was no relationship between MGMT and C13ORF18 expression and DNA methylation (χ2 = 0.776, P = 0.379 and χ2 = 1.411, P = 0.235, respectively). MBD2 protein level in cervical cancer was relatively lower than normal cervical tissue (t = 4.11, P = 0.006).Conclusions:HR-HPV detection is the cornerstone for triage setting of CIN. Promoter methylation of MGMT and C13ORF18 plays a limited role in triage of LSIL. Promoter methylation of both genes may not be the causes of gene silence.

Section: Discussionmentioning

confidence: 53%

“…[ 9 ] A study on methylation status of nine gene promoters revealed that methylation biomarkers distinguishing cervical precursor lesions from normal cervix were primarily C13ORF18 . [ 10 ] This study was designed to verify the efficacy of MGMT and C13ORF18 methylation and HR-HPV for the triage of cytology screening samples.…”

Section: Introductionmentioning

confidence: 99%

Limited Role of Promoter Methylation of MGMT and C13ORF18 in Triage of Low-Grade Squamous Intraepithelial Lesion

Liu

Chinese Medical Journal

et al. 2018

Mutation Research/Reviews in Mutation Research

“…However, hypermethylation of the TERT promoter was found to be significant in CIN3 lesions [107] and cervical cancer samples [108]. TERT promoter variants c.-146C > T and c.-124C > T were observed in 21.4% of cervical cancer patients in India, which is almost 4 times higher than the proportions reported by studies in Western populations [109].…”

Section: Senescence and Apoptosis Evasion Pathwaysmentioning

confidence: 73%

Putative biomarkers for cervical cancer: SNVs, methylation and expression profiles

Cardoso

Castelletti

Lima-Filho

et al. 2017

Cervical cancer is primarily caused by Human papillomavirus (HPV) infection, but other factors such as smoking habits, co-infections and genetic background, can also contribute to its development. Although this cancer is avoidable, it is the fourth most frequent type of cancer in females worldwide and can only be treated with chemotherapy and radical surgery. There is a need for biomarkers that will enable early diagnosis and targeted therapy for this type of cancer. Therefore, a systems biology pipeline was applied in order to identify potential biomarkers for cervical cancer, which show significant reports in three molecular aspects: DNA sequence variants, DNA methylation pattern and alterations in mRNA/protein expression levels. CDH1, CDKN2A, RB1 and TP53 genes were selected as putative biomarkers, being involved in metastasis, cell cycle regulation and tumour suppression. Other ten genes (CDH13, FHIT, PTEN, MLH1, TP73, CDKN1A, CACNA2D2, TERT, WIF1, APC) seemed to play a role in cervical cancer, but the lack of studies prevented their inclusion as possible biomarkers. Our results highlight the importance of these genes. However, further studies should be performed to elucidate the impact of DNA sequence variants and/or epigenetic deregulation and altered expression of these genes in cervical carcinogenesis and their potential as biomarkers for cervical cancer diagnosis and prognosis.

“…The other two studies were conducted in 2010 and 2015. Both studies found that normal tissue also had RAR β promoter methylation, which made it a poor predictor of progression to severe disease[ 62 , 64 ]. However, one of the two studies also investigated the level of methylation using quantitative methylation-specific PCR and found that although normal cells were methylated, the level of methylation increased in LSIL, HSIL, and invasive cancer tissue[ 62 ].…”

Section: Epigenetic Mechanisms and Risk Of Cancer Developmentmentioning

confidence: 99%

Retinoic acid receptor beta promoter methylation and risk of cervical cancer

Wongwarangkana

Wanlapakorn

Chansaenroj

et al. 2018

WJV

Cervical cancer is one of the leading causes of death in women worldwide, particularly in developing countries. Human papillomavirus has been reported as one of the key etiologic factors in cervical carcinoma. Likewise, epigenetic aberrations have ability to regulate cancer pathogenesis and progression. Recent research suggested that methylation has been detected already at precancerous stages, which methylation markers may have significant value in cervical cancer screening. The retinoic acid receptor beta (RARβ) gene, a potential tumor suppressor gene, is usually expressed in normal epithelial tissue. Methylation of CpG islands in the promoter region of the RARβ gene has been found to be associated with the development of cervical cancer. To investigate whether RARβ methylation is a potential biomarker that predicts the progression of invasive cancer, we reviewed 14 previously published articles related to RARβ methylation. The majority of them demonstrated that the frequency of RARβ promoter methylation was significantly correlated with the severity of cervical epithelium abnormalities. However, methylation of a single gene may not represent the best approach for predicting disease prognosis. Analyzing combinations of aberrant methylation of multiple genes may increase the sensitivity, and thus this approach may serve as a better tool for predicting disease prognosis.