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<p>DNA methylation is a critical epigenetic modification that regulates gene expression and plays a significant role in cancer development. This methylation signature can be detected in cancer-derived DNA from non-invasive samples, such as plasma, urine or Pap smears. However, in early-stage cancers—when detection is most critical—the concentration of cancer DNA is often low, limiting the sensitivity of current detection methods. Traditional DNA methylation detection techniques, which rely on methylation ratio-based measurements, may obscure subtle variations in methylation patterns, further reducing detection sensitivity. In this study, we analyzed cervical scraping specimens and examined whether detecting cancer-specific methylation patterns in cervical cancer could be enhanced using a Highly Methylated Haplotype (HMH) approach. This novel approach captures highly methylated haplotypes at single-molecule resolution using next-generation sequencing, providing greater detail than conventional methods. HMHs in specific DNA regions are a hallmark of cancer and stand out in contrast to sporadic methylation commonly observed in non-cancerous tissues. We applied HMH profiling to a gene panel of four biomarkers (<i>CA10</i>, <i>DPP10</i>, <i>FMN2</i>, and <i>HAS1</i>) previously validated in cervical cancer studies. At pre-specified cutoffs (99th percentile of normals), haplotype-based scoring achieved 89.9% sensitivity for invasive cancer at high specificity (~ 94–98%), outperforming median (78.0%) and single-CpG (71.6%) methods. For clinically relevant endpoints, the combined panel detected 51–52% of CIN2 + and 66–67% of CIN3 + cases, again exceeding the performance of median- and single-CpG-based scoring methods.</p><p>These findings demonstrate the potential of HMH to substantially enhance sensitivity in cervical cancer detection, offering a promising approach for non-invasive diagnostics.</p>

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Enhancing the sensitivity of non-invasive cervical cancer detection using CpG methylation haplotype profiling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月15日

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  • David Cheishvili,
  • Mariam El-Zein,
  • Eduardo L. Franco,
  • Moshe Szyf

摘要

DNA methylation is a critical epigenetic modification that regulates gene expression and plays a significant role in cancer development. This methylation signature can be detected in cancer-derived DNA from non-invasive samples, such as plasma, urine or Pap smears. However, in early-stage cancers—when detection is most critical—the concentration of cancer DNA is often low, limiting the sensitivity of current detection methods. Traditional DNA methylation detection techniques, which rely on methylation ratio-based measurements, may obscure subtle variations in methylation patterns, further reducing detection sensitivity. In this study, we analyzed cervical scraping specimens and examined whether detecting cancer-specific methylation patterns in cervical cancer could be enhanced using a Highly Methylated Haplotype (HMH) approach. This novel approach captures highly methylated haplotypes at single-molecule resolution using next-generation sequencing, providing greater detail than conventional methods. HMHs in specific DNA regions are a hallmark of cancer and stand out in contrast to sporadic methylation commonly observed in non-cancerous tissues. We applied HMH profiling to a gene panel of four biomarkers (CA10, DPP10, FMN2, and HAS1) previously validated in cervical cancer studies. At pre-specified cutoffs (99th percentile of normals), haplotype-based scoring achieved 89.9% sensitivity for invasive cancer at high specificity (~ 94–98%), outperforming median (78.0%) and single-CpG (71.6%) methods. For clinically relevant endpoints, the combined panel detected 51–52% of CIN2 + and 66–67% of CIN3 + cases, again exceeding the performance of median- and single-CpG-based scoring methods.

These findings demonstrate the potential of HMH to substantially enhance sensitivity in cervical cancer detection, offering a promising approach for non-invasive diagnostics.