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Comparison of HPV genotyping and methylated ZNF582 as triage for women with equivocal liquid-based cytology results.

Liou YL, Zhang Y, Liu Y, Cao L, Qin CZ, Zhang TL, Chang CF, Wang HJ, Lin SY, Chu TY, Zhang Y, Zhou HH - Clin Epigenetics (2015)

Bottom Line: However, the sensitivity and specificity of ZNF582 (m) combined with HPV-16/18 (both ZNF582 (m) and HPV-16/18 positive results) were 59.46% and 94.64%, respectively.To effectively manage ASC patients, a new strategy co-testing for ZNF582 (m) and HPV-16/18 genotyping was proposed.This strategy could reduce the number of patients referred for colposcopic examination and thus provide a feasible follow-up solution in the regions where colposcopy is not readily available.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, No. 110 Xiangya Road, Changsha, Hunan 410008 People's Republic of China ; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, No. 110 Xiangya Road, Changsha, Hunan 410078 People's Republic of China ; iStat Biomedical Co. Ltd., 18F, No. 96, Sec.1, Xintai 5th Road, Xizhi Dist., Taipei, 22102 Taiwan.

ABSTRACT

Introduction: The interpretation of equivocal Papanicolaou (Pap) smear results remains challenging, even with the addition of the high-risk human papillomavirus test (HPV-HR). Recently, methylated zinc finger protein 582 (ZNF582) (ZNF582 (m) ) was reported to be highly associated with cervical cancer. In this study, we compared the performance of ZNF582 (m) detection and HPV-HR genotyping in the triage of cervical atypical squamous cell of undetermined significance (ASC-US) and atypical squamous cell - cannot exclude a high-grade lesion (ASC-H).

Case description: Two hundred and forty-two subjects with equivocal papanicolaou smear (Pap smear) results were recruited in this hospital-based and case-controlled study. The residual cervical cells in liquid-based cytological test (LBC) containers were used for genomic DNA extraction and then for ZNF582 (m) and HPV-HR detection. The level of ZNF582 (m) was quantified by real-time methylation-specific PCR after bisulfite conversion. The HPV-HR test was performed by using a nested multiplex PCR (NMPCR) assay that combines degenerate E6/E7 consensus primers and HPV type-specific primers.

Discussion and evaluation: Significant associations were observed between ZNF582 (m) and the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+; odds ratio = 15.52, 95% confidence interval (CI): 7.73 to 31.18). The sensitivity and specificity of ZNF582 (m) for women with CIN3+ were 82.43% and 76.79%, respectively. High sensitivity (99.33%) but low specificity (38.76%) was observed for HPV-HR. When combining both positive results of ZNF582 (m) and HPV-HR, the sensitivity and specificity were 82.43% and 81.55%, respectively. The sensitivity and specificity of ZNF582 (m) or HPV-16/18 were 89.19% and 70.24%, respectively. However, the sensitivity and specificity of ZNF582 (m) combined with HPV-16/18 (both ZNF582 (m) and HPV-16/18 positive results) were 59.46% and 94.64%, respectively.

Conclusions: ZNF582 (m) provides a promising triage tool for women with ASC. To effectively manage ASC patients, a new strategy co-testing for ZNF582 (m) and HPV-16/18 genotyping was proposed. This strategy could reduce the number of patients referred for colposcopic examination and thus provide a feasible follow-up solution in the regions where colposcopy is not readily available. This strategy could also prevent women from experiencing unnecessary anxiety caused by HPV-HR.

No MeSH data available.


Related in: MedlinePlus

The recommended management of abnormal cervical cytology (Pap smear): a flowchart with methylated ZNF582m. ASC-H, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion; ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia 2; HPV, human papillomavirus-16/18; ZNF582, zinc finger protein 582; ZNF582m, methylated ZNF582.
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Fig2: The recommended management of abnormal cervical cytology (Pap smear): a flowchart with methylated ZNF582m. ASC-H, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion; ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia 2; HPV, human papillomavirus-16/18; ZNF582, zinc finger protein 582; ZNF582m, methylated ZNF582.

Mentions: Colposcopy is a diagnostic procedure performed by a physician to examine the cervix, vagina, and vulva carefully for signs of disease. Due to the high cost and insufficient availability of colposcopy, it is desirable to reduce the number of colposcopy referrals while still examining women with severe dysplasia or carcinoma such as CIN3, CIS, or SCC. Our results indicated that the referral rate for colposcopy for ZNF582m alone, HPV-HR alone, and ZNF582m, or HPV-16/18 are 41%, 73.1%, and 47.9% respectively (Table 1). Previous research has recommended triage procedures using HPV-HR followed by gene methylation screening [34]. Using HPV-HR testing as triage identified no CIN3 and SCC results in the study but the referral rate for colposcopy is 73.1%. If triaged using ZNF582m testing alone, the colposcopy referral would therefore reduce 31.8% compared to that of HPV-HR. However, only 61 out of the 74 women with CIN3+ and 4 SCC results would be detected. As a result, no treatment would be given to 17 women, who would be in a severe disease stage, especially the four with SCC. To avoid not detecting the severe cases, we have proposed a new strategy to manage ASC patients (Figure 2). This clinical flowchart has incorporated the ZNF582m and HPV testing into the procedures. Co-testing for ZNF582m and HPV-16/18 would therefore reduce 61 cases (25.21%) from colposcopy referral (when compared with HPV-HR), yet none of the SCC cases would be missed (Figure 2).Figure 2


Comparison of HPV genotyping and methylated ZNF582 as triage for women with equivocal liquid-based cytology results.

Liou YL, Zhang Y, Liu Y, Cao L, Qin CZ, Zhang TL, Chang CF, Wang HJ, Lin SY, Chu TY, Zhang Y, Zhou HH - Clin Epigenetics (2015)

The recommended management of abnormal cervical cytology (Pap smear): a flowchart with methylated ZNF582m. ASC-H, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion; ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia 2; HPV, human papillomavirus-16/18; ZNF582, zinc finger protein 582; ZNF582m, methylated ZNF582.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4419454&req=5

Fig2: The recommended management of abnormal cervical cytology (Pap smear): a flowchart with methylated ZNF582m. ASC-H, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion; ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia 2; HPV, human papillomavirus-16/18; ZNF582, zinc finger protein 582; ZNF582m, methylated ZNF582.
Mentions: Colposcopy is a diagnostic procedure performed by a physician to examine the cervix, vagina, and vulva carefully for signs of disease. Due to the high cost and insufficient availability of colposcopy, it is desirable to reduce the number of colposcopy referrals while still examining women with severe dysplasia or carcinoma such as CIN3, CIS, or SCC. Our results indicated that the referral rate for colposcopy for ZNF582m alone, HPV-HR alone, and ZNF582m, or HPV-16/18 are 41%, 73.1%, and 47.9% respectively (Table 1). Previous research has recommended triage procedures using HPV-HR followed by gene methylation screening [34]. Using HPV-HR testing as triage identified no CIN3 and SCC results in the study but the referral rate for colposcopy is 73.1%. If triaged using ZNF582m testing alone, the colposcopy referral would therefore reduce 31.8% compared to that of HPV-HR. However, only 61 out of the 74 women with CIN3+ and 4 SCC results would be detected. As a result, no treatment would be given to 17 women, who would be in a severe disease stage, especially the four with SCC. To avoid not detecting the severe cases, we have proposed a new strategy to manage ASC patients (Figure 2). This clinical flowchart has incorporated the ZNF582m and HPV testing into the procedures. Co-testing for ZNF582m and HPV-16/18 would therefore reduce 61 cases (25.21%) from colposcopy referral (when compared with HPV-HR), yet none of the SCC cases would be missed (Figure 2).Figure 2

Bottom Line: However, the sensitivity and specificity of ZNF582 (m) combined with HPV-16/18 (both ZNF582 (m) and HPV-16/18 positive results) were 59.46% and 94.64%, respectively.To effectively manage ASC patients, a new strategy co-testing for ZNF582 (m) and HPV-16/18 genotyping was proposed.This strategy could reduce the number of patients referred for colposcopic examination and thus provide a feasible follow-up solution in the regions where colposcopy is not readily available.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, No. 110 Xiangya Road, Changsha, Hunan 410008 People's Republic of China ; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, No. 110 Xiangya Road, Changsha, Hunan 410078 People's Republic of China ; iStat Biomedical Co. Ltd., 18F, No. 96, Sec.1, Xintai 5th Road, Xizhi Dist., Taipei, 22102 Taiwan.

ABSTRACT

Introduction: The interpretation of equivocal Papanicolaou (Pap) smear results remains challenging, even with the addition of the high-risk human papillomavirus test (HPV-HR). Recently, methylated zinc finger protein 582 (ZNF582) (ZNF582 (m) ) was reported to be highly associated with cervical cancer. In this study, we compared the performance of ZNF582 (m) detection and HPV-HR genotyping in the triage of cervical atypical squamous cell of undetermined significance (ASC-US) and atypical squamous cell - cannot exclude a high-grade lesion (ASC-H).

Case description: Two hundred and forty-two subjects with equivocal papanicolaou smear (Pap smear) results were recruited in this hospital-based and case-controlled study. The residual cervical cells in liquid-based cytological test (LBC) containers were used for genomic DNA extraction and then for ZNF582 (m) and HPV-HR detection. The level of ZNF582 (m) was quantified by real-time methylation-specific PCR after bisulfite conversion. The HPV-HR test was performed by using a nested multiplex PCR (NMPCR) assay that combines degenerate E6/E7 consensus primers and HPV type-specific primers.

Discussion and evaluation: Significant associations were observed between ZNF582 (m) and the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+; odds ratio = 15.52, 95% confidence interval (CI): 7.73 to 31.18). The sensitivity and specificity of ZNF582 (m) for women with CIN3+ were 82.43% and 76.79%, respectively. High sensitivity (99.33%) but low specificity (38.76%) was observed for HPV-HR. When combining both positive results of ZNF582 (m) and HPV-HR, the sensitivity and specificity were 82.43% and 81.55%, respectively. The sensitivity and specificity of ZNF582 (m) or HPV-16/18 were 89.19% and 70.24%, respectively. However, the sensitivity and specificity of ZNF582 (m) combined with HPV-16/18 (both ZNF582 (m) and HPV-16/18 positive results) were 59.46% and 94.64%, respectively.

Conclusions: ZNF582 (m) provides a promising triage tool for women with ASC. To effectively manage ASC patients, a new strategy co-testing for ZNF582 (m) and HPV-16/18 genotyping was proposed. This strategy could reduce the number of patients referred for colposcopic examination and thus provide a feasible follow-up solution in the regions where colposcopy is not readily available. This strategy could also prevent women from experiencing unnecessary anxiety caused by HPV-HR.

No MeSH data available.


Related in: MedlinePlus