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Background <p>Cervical cancer remains a significant global health burden, and effective triage strategies are urgently needed for high-risk human papillomavirus (hrHPV)-positive women in screening programs. This study aimed to identify and validate DNA methylation markers for detecting cervical precancerous lesions in hrHPV-positive women.</p> Methods <p>Reduced representation bisulfite sequencing (RRBS) was performed on a discovery cohort (<i>n</i> = 17) to screen for differentially methylated candidate genes. Quantitative methylation-specific PCR (qMSP) was used to evaluate the performance of selected markers in an independent cohort of 347 hrHPV-positive women stratified into training (<i>n</i> = 154) and validation (<i>n</i> = 193) sets. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) curves, sensitivity, specificity, and area under the curve (AUC).</p> Results <p>Among the candidates identified, <i>CNTNAP2</i> and <i>PAX1</i> methylation levels increased progressively with cervical disease severity (both <i>P</i> &lt; 0.0001). In the independent validation set, the combined <i>CNTNAP2/PAX1</i> panel achieved an AUC of 0.904 (95% CI: 0.853–0.942) for CIN2 + detection and 0.932 (95% CI: 0.887–0.963) for CIN3 + detection. The panel yielded a sensitivity of 73.8% and specificity of 95.5% for CIN2+, and a sensitivity of 89.2% and specificity of 87.8% for CIN3+. In comparison, HPV16/18 genotyping showed sensitivities of 54.1% for CIN2 + and 56.8% for CIN3+, with specificities of 81.1% and 76.3%, respectively. Cytology (≥ ASCUS) had higher sensitivity (CIN2+: 93.1%; CIN3+: 91.2%) but substantially lower specificity (CIN2+: 16.9%; CIN3+: 14.9%); notably, cytology specificity in this cohort was likely underestimated due to verification bias. The <i>CNTNAP2/PAX1</i> panel outperformed both comparator methods in overall diagnostic accuracy.</p> Conclusions <p>The <i>CNTNAP2/PAX1</i> methylation panel demonstrates robust diagnostic performance for detecting cervical precancerous lesions in hrHPV-positive women, supporting its potential utility as an objective and effective triage tool in hrHPV-based cervical cancer screening.</p>

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Identification and validation of CNTNAP2/PAX1 hypermethylation as an epigenetic biomarker panel for detection of cervical cancer and precancerous lesions in hrHPV-positive women

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Yuying He,
  • Haiyan Yang,
  • Chuang Zhang,
  • Ruiwei Jiang,
  • Kai Kang,
  • Yuxue Wang,
  • Dixian Luo,
  • Dan Xiong

摘要

Background

Cervical cancer remains a significant global health burden, and effective triage strategies are urgently needed for high-risk human papillomavirus (hrHPV)-positive women in screening programs. This study aimed to identify and validate DNA methylation markers for detecting cervical precancerous lesions in hrHPV-positive women.

Methods

Reduced representation bisulfite sequencing (RRBS) was performed on a discovery cohort (n = 17) to screen for differentially methylated candidate genes. Quantitative methylation-specific PCR (qMSP) was used to evaluate the performance of selected markers in an independent cohort of 347 hrHPV-positive women stratified into training (n = 154) and validation (n = 193) sets. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) curves, sensitivity, specificity, and area under the curve (AUC).

Results

Among the candidates identified, CNTNAP2 and PAX1 methylation levels increased progressively with cervical disease severity (both P < 0.0001). In the independent validation set, the combined CNTNAP2/PAX1 panel achieved an AUC of 0.904 (95% CI: 0.853–0.942) for CIN2 + detection and 0.932 (95% CI: 0.887–0.963) for CIN3 + detection. The panel yielded a sensitivity of 73.8% and specificity of 95.5% for CIN2+, and a sensitivity of 89.2% and specificity of 87.8% for CIN3+. In comparison, HPV16/18 genotyping showed sensitivities of 54.1% for CIN2 + and 56.8% for CIN3+, with specificities of 81.1% and 76.3%, respectively. Cytology (≥ ASCUS) had higher sensitivity (CIN2+: 93.1%; CIN3+: 91.2%) but substantially lower specificity (CIN2+: 16.9%; CIN3+: 14.9%); notably, cytology specificity in this cohort was likely underestimated due to verification bias. The CNTNAP2/PAX1 panel outperformed both comparator methods in overall diagnostic accuracy.

Conclusions

The CNTNAP2/PAX1 methylation panel demonstrates robust diagnostic performance for detecting cervical precancerous lesions in hrHPV-positive women, supporting its potential utility as an objective and effective triage tool in hrHPV-based cervical cancer screening.