Research Papers:

Utility of gene methylation analysis, cytological examination, and HPV-16/18 genotyping in triage of high-risk human papilloma virus-positive women

Yan Tian, Na-Yi Yuan Wu, Yu-Ligh Liou, Ching-Tung Yeh, Lanqin Cao, Ya-Nan Kang, Huei-Jen Wang, Yichen Li, Tang-Yuan Chu, Wei Li, Xiang Liu, Yi Zhang, Honghao Zhou and Yu Zhang _

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Oncotarget. 2017; 8:62274-62285. https://doi.org/10.18632/oncotarget.19459

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Yan Tian1,*, Na-Yi Yuan Wu2,3,*, Yu-Ligh Liou2,3,4, Ching-Tung Yeh4, Lanqin Cao1, Ya-Nan Kang1, Huei-Jen Wang4, Yichen Li4, Tang-Yuan Chu5, Wei Li6, Xiang Liu7, Yi Zhang1, Honghao Zhou2,3,* and Yu Zhang1,*

1Department of Obstetrics & Gynecology, Xiangya Hospital, Hunan, P. R. China

2Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China

3Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China

4iStat Biomedical Co. Ltd., Taipei, Taiwan

5Department of Obstetrics & Gynecology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan

6Department of Obstetrics and Gynecology, ShengJing Hospital of China Medical University, Liaoning, P. R. China

7Department of Pharmacy, Xiangtan Central Hospital, Xiangtan, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Yu Zhang, email: [email protected]

Honghao Zhou, email: [email protected]

Keywords: HPV triage, PAX1, ZNF582, HPV16/18 genotyping, cervical cancer

Received: June 11, 2016    Accepted: May 11, 2017    Published: July 22, 2017


In 2015, the American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology issued interim guidance for the use of a human papillomavirus (HPV) test for primary screening, suggesting triage of women positive for high-risk human papillomavirus (hrHPV) by HPV-16/18 genotyping and cytology for women positive for non-16/18 hrHPV. The design of the present study was based on this interim guidance and analysis of the methylation status of specific candidate genes, which has been proposed as a tool to reduce unnecessary referral following primary HPV screening for cervical cancer. We performed a hospital-based case-control study including 312 hrHPV-positive women. hrHPV genotyping was performed by nested multiplex PCR assay with type-specific primers.Residual cervical cells from liquid-based cytology were used for extraction of genomic DNA for assessment of the methylation status of PAX1, ZNF582, SOX1, and NKX6-1 and HPV genotyping. Combined with HPV-16/18 genotyping, both a dual methylation test for PAX1/ZNF582 and testing for ZNF582 methylation demonstrated 100% association of methylation with pathology results, indicating carcinoma in situ or squamous cell carcinoma. The sensitivity and specificity of the dual methylation test for PAX1/ZNF582 as a reflex test for identification of CIN3+ lesions were 78.85% and 73.55% (odds ratio = 10.37, 95% confidence interval = 4.76–22.58), respectively. This strategy could reduce the number of patients referred for colposcopic examination by 31.3% compared with cytology, and thus provide a feasible follow-up solution in regions where colposcopy is not readily available. This strategy could also prevent unnecessary anxiety in women with hrHPV infection.

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