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Background <p>Although human papillomavirus (HPV) testing and Thin-Prep Cytology Test (TCT) are currently adopted as the first-line screening methods for cervical cancer, both of them have limitations. This study aimed to&#xa0;develop and validate new methylation-based biomarkers from formalin-fixed paraffin-embedded (FFPE) tissue and TCT samples in a Chinese population to improve early detection of cervical cancer (CC).</p> Methods <p>We performed a differential methylation analysis of cervical FFPE tissues and TCT samples through targeted methylation sequencing. Quantitative methylation-specific PCR (qMSP) was performed on cervical tissues, TCT samples and cell lines to construct a diagnostic model containing three highly methylated sites, namely <i>JAM3</i>, <i>VSTM2B</i> and <i>EPHA7</i>. The clinical effectiveness was evaluated on overall 279 TCT multiple group samples, comprising 33 squamous cell carcinomas (SCC), 14 adenocarcinoma(ADC), 43 high-grade squamous intraepithelial lesion (HSIL), 49 low-grade squamous intraepithelial lesion (LSIL), 78 high risk-HPV (HR-HPV)–positive/cytology-normal (NILM) cases, 32 healthy controls (NC), and 30 benign gynecological samples. The model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUC).</p> Results <p>In an independent validation cohort (n = 108), the panel of three methylation-based biomarkers showed outstanding diagnostic accuracy. It achieved sensitivities of 100.0% for SCC (n = 10), 80.0% for ADC (n = 5), and 86.7% for HSIL (n = 15). Specificity was 90.6% in HR-HPV–positive women (n = 32), 100.0% in NC (n = 12), and 93.3% in other benign conditions (n = 15), with 89.5% specificity in LSIL (n = 19). Overall sensitivity and specificity were 90.0% and 92.3%, respectively. HPV subtype–stratified analysis revealed 90.9% sensitivity and 85.7% specificity for HPV16/18–positive samples, with consistent performance for non-HPV16/18 subtypes (85.7% sensitivity, 89.5% specificity).</p> Conclusions <p>The <i>JAM3/VSTM2B/EPHA7</i> methylation model (<i>JAM3</i><sup><i>m</i></sup><i>/VSTM2B</i><sup><i>m</i></sup><i>/EPHA7</i><sup><i>m</i></sup>) has shown excellent performance in the detection of cervical cancer and precancerous lesions. It provides a new direction for overcoming the limitations of the traditional HPV and TCT combined screening method.</p>

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Methylation-based biomarkers from thin-prep cytology test samples for early detection of cervical cancer: application and clinical potential

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Zhihan Liu,
  • Guorong Liu,
  • Shuanping Liu,
  • Xiuxiu Wang,
  • Yunshi Liang,
  • Yuanyuan Guo,
  • Baochen Du,
  • Nabo Miao,
  • Wenli Shi,
  • Qiuyun Zhu,
  • Liping Yu,
  • Cui Deng,
  • Guo Chen,
  • Lijuan Huang,
  • Lingling Zhan,
  • Xiangyu Zheng,
  • Jie Zhao,
  • Yongjun Li,
  • Xiaoliang Han,
  • Yang Cheng,
  • Jing Yang

摘要

Background

Although human papillomavirus (HPV) testing and Thin-Prep Cytology Test (TCT) are currently adopted as the first-line screening methods for cervical cancer, both of them have limitations. This study aimed to develop and validate new methylation-based biomarkers from formalin-fixed paraffin-embedded (FFPE) tissue and TCT samples in a Chinese population to improve early detection of cervical cancer (CC).

Methods

We performed a differential methylation analysis of cervical FFPE tissues and TCT samples through targeted methylation sequencing. Quantitative methylation-specific PCR (qMSP) was performed on cervical tissues, TCT samples and cell lines to construct a diagnostic model containing three highly methylated sites, namely JAM3, VSTM2B and EPHA7. The clinical effectiveness was evaluated on overall 279 TCT multiple group samples, comprising 33 squamous cell carcinomas (SCC), 14 adenocarcinoma(ADC), 43 high-grade squamous intraepithelial lesion (HSIL), 49 low-grade squamous intraepithelial lesion (LSIL), 78 high risk-HPV (HR-HPV)–positive/cytology-normal (NILM) cases, 32 healthy controls (NC), and 30 benign gynecological samples. The model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUC).

Results

In an independent validation cohort (n = 108), the panel of three methylation-based biomarkers showed outstanding diagnostic accuracy. It achieved sensitivities of 100.0% for SCC (n = 10), 80.0% for ADC (n = 5), and 86.7% for HSIL (n = 15). Specificity was 90.6% in HR-HPV–positive women (n = 32), 100.0% in NC (n = 12), and 93.3% in other benign conditions (n = 15), with 89.5% specificity in LSIL (n = 19). Overall sensitivity and specificity were 90.0% and 92.3%, respectively. HPV subtype–stratified analysis revealed 90.9% sensitivity and 85.7% specificity for HPV16/18–positive samples, with consistent performance for non-HPV16/18 subtypes (85.7% sensitivity, 89.5% specificity).

Conclusions

The JAM3/VSTM2B/EPHA7 methylation model (JAM3m/VSTM2Bm/EPHA7m) has shown excellent performance in the detection of cervical cancer and precancerous lesions. It provides a new direction for overcoming the limitations of the traditional HPV and TCT combined screening method.