Methylated ZNF582 gene as a marker for triage of women with Pap smear reporting low-grade squamous intraepithelial lesions — A Taiwanese Gynecologic Oncology Group (TGOG) study

Lin, Hao; Chen, Tze Chien; Chang, Ting Chang; Cheng, Ya Min; Chen, Chi Hau; Chu, Tang-Yuan; Hsu, Shih Tien; Liu, Cheng Bin; Yeh, Lian Shung; Wen, Kuo Chang; Huang, Chia-Yen; Mu, Yu

doi:10.1016/j.ygyno.2014.08.012

Cited by 31 publications

(29 citation statements)

References 40 publications

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“…Here, we found that the FAM19A4 marker alone had a similar performance in terms of CIN2þ, CIN3þ, and cervical carcinoma detection as a panel of previously studied methylation markers (11). Recently, other single methylation markers, i.e., PAX1 and ZNF582, have been reported as a promising methylation markers for cervical screening and women with LSIL, respectively (30,31). Yet, these markers have not been validated in population-based screening studies and require further investigation.…”

Section: Discussionsupporting

confidence: 56%

Methylation Analysis of the FAM19A4 Gene in Cervical Scrapes Is Highly Efficient in Detecting Cervical Carcinomas and Advanced CIN2/3 Lesions

Strooper

Meijer

Berkhof

et al. 2014

Cancer Prevention Research

108

154

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Primary testing for human papillomavirus (HPV) in cervical screening requires triage to differentiate women with transient infection from those with persistent infection who require more intensive management given their risk for cervical (pre)cancer. In this study, the clinical performance of a novel methylation marker FAM19A4 for the triage of high-risk (hr)HPV-positive women was evaluated. Using a trainingvalidation set approach, we analyzed a FAM19A4 quantitative methylation-specific PCR (qMSP). The training set comprised hrHPV-positive cervical scrapes of 43 women with cervical intraepithelial neoplasia grade 3 or worse (CIN3þ) and 135 women with CIN1. The validation set comprised hrHPV-positive cervical scrapes of 52 women with CIN2þ, including 33 CIN3þ, 19 CIN2, and 166 women with CIN1. The methylation threshold of FAM19A4 qMSP that gave rise to CIN3þ specificity of 70% in the training set was applied in the validation set. This resulted in CIN3þ sensitivity of 75.8% [95% confidence interval (CI), 61.1-90.4] at 67.0% (95% CI, 60.3-73.8) specificity. Next, the validated qMSP was applied to an independent series of hrHPV-positive cervical scrapes of 22 women with cervical cancer, 29 with advanced CIN2/3 [i.e., women with a known preceding hrHPV infection (PHI) lasting !5 years as proxy of longer duration of lesion existence], and 19 with early CIN2/3 (i.e., PHI <5 years). All carcinomas (22/22) and advanced CIN2/3 lesions (29/29) were FAM19A4 methylation-positive, compared with 42.1% (8/19; 95% CI, 19.9-64.3) of early CIN2/3 lesions. In conclusion, FAM19A4 is an attractive triage marker for hrHPVpositive women, with a high reassurance for the detection of cervical carcinoma and advanced CIN2/3 lesions. Cancer Prev Res; 7(12); 1251-7. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 56%

Methylation Analysis of the FAM19A4 Gene in Cervical Scrapes Is Highly Efficient in Detecting Cervical Carcinomas and Advanced CIN2/3 Lesions

Strooper

Meijer

Berkhof

et al. 2014

Cancer Prevention Research

108

154

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“…Consistent with the concept that ZNF582 is a tumor suppressor, ZNF582 hypermethylation has been reported in acute myeloid leukemia and various invasive cancers [37]. Liou et al reported that ZNF582 methylation testing had a 70% sensitivity and an 82% specificity for the detection of cervical cancer CIN3+ lesions [37], and a great sensitivity and specificity in the classification of low-grade squamous intraepithelial lesion (LSIL) [20]. In the present study, we demonstrated that ZNF582 gene was much more frequently methylated in ESCC tumor tissues compared to non-tumor paracancerous tissues.…”

Section: Discussionmentioning

confidence: 76%

“…Previous studies have shown that the methylation status of PAX1 and ZNF582 genes is a useful testing to distinguish tumor and non-tumor tissues in cervical and oral squamous cell carcinoma [19,20]. In the present study, we have for the first time demonstrated that the levels and frequencies of PAX1 and ZNF582 methylation are markedly higher in the tumor tissues compared to non-tumor tissues from ESCC patients, and methylation testing of these two genes has an excellent accuracy and great sensitivity and specificity to detect ESCC tumors, suggesting that PAX1 and ZNF582 methylation testing may be a promising biomarker for the detection of ESCC.…”

Section: Discussionmentioning

confidence: 99%

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DNA Methylation Status of PAX1 and ZNF582 in Esophageal Squamous Cell Carcinoma

Huang

Guo

Tang

et al. 2017

IJERPH

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Hypermethylation of specific gene promoters is an important mechanism of carcinogenesis. A high frequency of promoter methylation of PAX1 and ZNF582 genes has been detected in cervical cancer. In the present study, we investigated the methylation status of PAX1 and ZNF582 genes in esophageal squamous cell carcinoma (ESCC) tissues. Tumor and paracancerous tissues were obtained from 14 ESCC patients. Genomic DNA was extracted from both tumor and paracancerous tissues, and the concentration of DNA were determined. DNA methylation analysis of PAX1 and ZNF582 genes was carried out using quantitative methylation-specific PCR. To assess the diagnostic performance of the two methylated genes for cancer detection, receiver operating characteristic (ROC) curves were generated. Sensitivities and specificities were tested at cut-offs obtained from the ROC curves. The methylation levels of both PAX1 and ZNF582 genes were significantly higher in tumor tissues compared to non-tumor paracancerous tissues. The methylation rates of PAX1 and ZNF582 in ESCC tumor and paracancerous tissues were 100% and 21.4% (p = 0.006), 85.7% and 0% (p < 0.001), respectively. The sensitivities and specificities of PAX1 and ZNF582 methylation for the detection of cancer were 100% and 85.7%, and 78.6% and 100%, respectively. The DNA methylation levels and frequencies of PAX1 and ZNF582 genes were markedly higher in ESCC tumor tissues compared to those in paracancerous tissues. Moreover, the conclusions were verified by using The Cancer Genome Atlas (TCGA) datasets. DNA methylation status of these two genes showed a relatively good sensitivity and specificity for the detection of ESCC tumors. This data suggests that DNA methylation testing holds a great promise for ESCC screening and warrants further prospective population-based studies.

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“…The promise of methylation analysis for early detection of cervical neoplasia is widely acknowledged 15–18 23–27 33–35 45 46. At present, methylation analysis is proposed as a triage test for HPV-positive women, with clinical utility in detection of CIN2+/3+ shown for both hrHPV-positive cervical scrapes33 37 and self-collected specimens 34 35.…”

Section: Discussionmentioning

confidence: 99%

CADM1,MALandmiR124-2methylation analysis in cervical scrapes to detect cervical and endometrial cancer

et al. 2014

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Aims Gene promoter hypermethylation is recognized as an essential early step in carcinogenesis, indicating important application areas for DNA methylation analysis in early cancer detection. The current study was set out to assess the performance of CADM1, MAL and miR124-2 methylation analysis in cervical scrapes for detection of cervical and endometrial cancer.Methods A series of cervical scrapes of women with cervical (n=79) or endometrial (n=21) cancer, CIN3 (n=16) or CIN2 (n= 32), and women without evidence of CIN2 or worse (n=120), was assessed for methylation of CADM1, MAL and miR124-2. Methylation analysis was done by the PreCursor-M assay, a multiplex quantitative methylation-specific PCR.Results All samples of women with cervical cancer (79/79, 100%), independent of the histotype, and 76% (16/21; 95% CI:58.0-94.4) of women with endometrial cancer scored positive for DNA methylation of at least one of the three genes. In women without cancer, methylation frequencies increased significantly to severity of disease, from 19.2% (23/120; 95% CI:12.1-26.2) in women without CIN2 or worse to 37.5% (12/32; 95% CI: 20.7-54.3) and 68.8% (11/16; 95% CI:46.0-91.5) in women with CIN2 and CIN3, respectively. Not only overall methylation positivity, but also the number of methylated genes increased proportionally to the lesion severity.Conclusions DNA methylation analysis of CADM1, MAL and miR124-2 in cervical scrapes consistently detects cervical cancer and the majority of CIN3 lesions, and has the capacity to broaden its use on cervical scrapes through the detection of a substantial subset of endometrial carcinomas.

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Methylated ZNF582 gene as a marker for triage of women with Pap smear reporting low-grade squamous intraepithelial lesions — A Taiwanese Gynecologic Oncology Group (TGOG) study

Cited by 31 publications

References 40 publications

Methylation Analysis of the FAM19A4 Gene in Cervical Scrapes Is Highly Efficient in Detecting Cervical Carcinomas and Advanced CIN2/3 Lesions

Methylation Analysis of the FAM19A4 Gene in Cervical Scrapes Is Highly Efficient in Detecting Cervical Carcinomas and Advanced CIN2/3 Lesions

DNA Methylation Status of PAX1 and ZNF582 in Esophageal Squamous Cell Carcinoma

CADM1,MALandmiR124-2methylation analysis in cervical scrapes to detect cervical and endometrial cancer

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