Triage of high-risk human papillomavirus-positive women by methylated POU4F3

Par Bahadur Pun, Yu Ping Liao, Po Hsuan Su, Hui Chen Wang, Yu Chih Chen, Yaw Wen Hsu, Rui Lan Huang, Cheng Chang Chang, Hung Cheng Lai

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Abstract

Background: Insufficient specificity of the high-risk human papillomavirus (hrHPV) assay in primary cervical cancer screening results in unnecessary referral. Additional assays to triage hrHPV-positive women are needed to improve molecular cervical cancer screening. DNA methylation is a promising biomarker in cervical cancer. We evaluated the clinical performance of potentially methylated genes as a triage assay for hrHPV-positive women. Results: We conducted a retrospective hospital-based case–control study in Taiwan. Cervical scrapings were collected before colposcopy for hrHPV testing and quantitative methylation-specific PCR (QMSP) of 16 genes. Five genes, POU4F3, HS3ST2, AJAP1, PAX1, and SOX1, were prioritized for the clinical performance to triage hrHPV-positive women. Two hundred cervical scrapings were randomly classified into a training set (n = 111) and testing set (n = 89). All samples were tested for hrHPV using a Hybrid Capture II (HCII) assay. HrHPV-positive women were subjected to DNA methylation analysis by QMSP. In the training set, the receiver operating characteristic (ROC) curves defined the optimal methylation index (M-index) cutoff values for discriminating CIN3+ from CIN1/normal, which then were applied to the testing set. Among the five genes, POU4F3 revealed the highest area under the ROC curve (AUC) (0.86; 95 % CI, 0.78–0.95) in detecting CIN3+. In the testing set, POU4F3 revealed the best clinical performance in triage of hrHPV-positive women with a sensitivity of 74 % and specificity of 89 % for detecting CIN3+. Conclusions: POU4F3 methylation analysis is a potential molecular tool for triage in detecting CIN3+ in hrHPV-positive women. The combined use of broad-spectrum HPV assay and POU4F3 methylation analysis as a new generation of molecular cervical cancer screening warrants further population-based study.

Original languageEnglish
Article number85
JournalClinical Epigenetics
Volume7
Issue number1
DOIs
Publication statusPublished - Aug 21 2015

Keywords

  • Biomarker
  • Cervical cancer screening
  • Cervical intraepithelial neoplasia (CIN)
  • DNA methylation
  • HrHPV test
  • QMSP

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Developmental Biology
  • Genetics(clinical)

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    Pun, P. B., Liao, Y. P., Su, P. H., Wang, H. C., Chen, Y. C., Hsu, Y. W., Huang, R. L., Chang, C. C., & Lai, H. C. (2015). Triage of high-risk human papillomavirus-positive women by methylated POU4F3. Clinical Epigenetics, 7(1), [85]. https://doi.org/10.1186/s13148-015-0122-0