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Background <p>DNA methylation analysis provides a promising triage strategy for cervical intraepithelial neoplasia (CIN) and cancer detection following Human Papillomavirus (HPV) testing on self-collected samples, including urine.</p> Methods <p>This study aimed to develop an entirely molecular cervical screening approach based on HPV and DNA methylation analysis in at-home collected first-void urine from healthy females (<i>n </i>= 69) and a referral population (<i>n </i>= 385; CIN-cancer). CIN3+ detection was analyzed by multivariate logistic regression.</p> Results <p>Here we show that urinary <i>ASCL1/LHX8</i> methylation levels increase significantly in relation to disease severity, with AUC-values for CIN3+ of 0.81 (95%&#xa0;CI:&#xa0;0.74–0.88) and 0.83 (95%&#xa0;CI:&#xa0;0.74–0.92) in the training (<i>n </i>= 285) and validation cohort (<i>n </i>= 160), respectively. This corresponds to a validated CIN3+ sensitivity of 73.0% (95%&#xa0;CI:&#xa0;57.0–84.6%) at 81.9% specificity (95%&#xa0;CI:&#xa0;73.5–88.1%; &lt;CIN2). Urinary HPV testing is more sensitive (83.8%; 95%&#xa0;CI:&#xa0;68.9–92.3%) although less specific (59.6%;&#xa0;95%&#xa0;CI: 50.0–68.5%). For triage of HPV positives, <i>ASCL1/LHX8</i> methylation and HPV16/18 genotyping have a similar CIN3+ sensitivity (75.0%; 95%&#xa0;CI:&#xa0;62.8–84.2% vs 73.3%; 95%&#xa0;CI:&#xa0;61.0–82.9%), with lower genotyping specificity. Combining <i>ASCL1/LHX8</i> methylation with HPV16/18 genotyping yield a 85.0% sensitivity (95%&#xa0;CI:&#xa0;73.9–91.9%) at 50.5% specificity (95%&#xa0;CI:&#xa0;40.8–60.1%).</p> Conclusions <p>The <i>ASCL1/LHX8</i> methylation test detects nearly all cancers and a majority of CIN3 in first-void urine, supporting the potential of full molecular screening in urine by primary HPV testing and methylation triage.</p>

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Clinical performance of ASCL1/LHX8 DNA methylation on first-void urine to screen for cervical cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • Severien Van Keer,
  • Rianne van den Helder,
  • Laura Téblick,
  • Annemie De Smet,
  • Gilbert Donders,
  • Steven Weyers,
  • Jean Doyen,
  • Nienke van Trommel,
  • Constantijne H. Mom,
  • Harold Verhoeve,
  • Chris J. L. M. Meijer,
  • Maaike Bleeker,
  • Ann Cornelis,
  • Koen Van de Vijver,
  • Katty Delbecque,
  • Birgit Lissenberg-Witte,
  • Alex Vorsters,
  • Renske D. M. Steenbergen

摘要

Background

DNA methylation analysis provides a promising triage strategy for cervical intraepithelial neoplasia (CIN) and cancer detection following Human Papillomavirus (HPV) testing on self-collected samples, including urine.

Methods

This study aimed to develop an entirely molecular cervical screening approach based on HPV and DNA methylation analysis in at-home collected first-void urine from healthy females (n = 69) and a referral population (n = 385; CIN-cancer). CIN3+ detection was analyzed by multivariate logistic regression.

Results

Here we show that urinary ASCL1/LHX8 methylation levels increase significantly in relation to disease severity, with AUC-values for CIN3+ of 0.81 (95% CI: 0.74–0.88) and 0.83 (95% CI: 0.74–0.92) in the training (n = 285) and validation cohort (n = 160), respectively. This corresponds to a validated CIN3+ sensitivity of 73.0% (95% CI: 57.0–84.6%) at 81.9% specificity (95% CI: 73.5–88.1%; <CIN2). Urinary HPV testing is more sensitive (83.8%; 95% CI: 68.9–92.3%) although less specific (59.6%; 95% CI: 50.0–68.5%). For triage of HPV positives, ASCL1/LHX8 methylation and HPV16/18 genotyping have a similar CIN3+ sensitivity (75.0%; 95% CI: 62.8–84.2% vs 73.3%; 95% CI: 61.0–82.9%), with lower genotyping specificity. Combining ASCL1/LHX8 methylation with HPV16/18 genotyping yield a 85.0% sensitivity (95% CI: 73.9–91.9%) at 50.5% specificity (95% CI: 40.8–60.1%).

Conclusions

The ASCL1/LHX8 methylation test detects nearly all cancers and a majority of CIN3 in first-void urine, supporting the potential of full molecular screening in urine by primary HPV testing and methylation triage.