bims-dinmec Biomed News
on DNA methylation in cancer
Issue of 2026–03–29
two papers selected by
Lorena Ancona, Humanitas Research
  1. MPCI: A novel metric for quantifying DNA methylation patterns in NGS data.
  2. Liquid biopsy biomarkers for early detection of gastrointestinal cancers: Current landscape and emerging technologies.
  1. PLoS Comput Biol. 2026 Mar 24. 22(3): e1014076
    MPCI: A novel metric for quantifying DNA methylation patterns in NGS data.
    Naghme Nazer, Hoda Mohammadzade, Mahya Mehrmohamadi.
      Epigenetic processes, particularly disruptions in DNA methylation profiles, are associated with many disease states. Traditional approaches for DNA methylation biomarker discovery focusing on individual CpG sites do not account for fragment-level methylation states. Methylation haplotype analysis offers a more comprehensive approach leading to increased distinction capability between reads originating from tissues with diverse methylation profiles. This can particularly be valuable in liquid biopsy where detecting small amounts of disease-specific cell-free DNA (cfDNA) amidst a bulk of healthy cfDNA is challenging. To address limitations of existing metrics for quantifying methylation patterns in a region, we propose the Methylation Pattern Consistency Index (MPCI), a novel metric that captures consistent methylation patterns across sequencing reads, accounting for both methylated and unmethylated blocks of CpGs. Using whole-genome bisulfite sequencing data, we demonstrate that MPCI outperforms MHL and its symmetric counterpart, dMHL (MHL - uMHL), across several benchmarks: distinguishing closely related cell types (CD4 vs. CD8; AUC 0.915), multi-tissue classification (0.92 accuracy), and detection of in-silico cfDNA spike-ins at abundances as low as 1%. Notably, in a clinical liquid-biopsy cohort of liver transplant patients, MPCI achieved significantly higher classification performance than dMHL (Accuracy: MPCI: 0.868 ± 0.023 vs. dMHL: 0.768 ± 0.027, p = 0.014) in discriminating pre- from post-transplant cfDNA profiles. These findings position MPCI as a reliable quantification approach for biomarker selection or diagnostic testing in epigenetic studies. We have made MPCI available as an R function for usage convenience.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014076
  2. Clin Transl Med. 2026 Mar;16(3): e70594
    Liquid biopsy biomarkers for early detection of gastrointestinal cancers: Current landscape and emerging technologies.
    Muhammad Anees, Christopher Sherry, Hyun Y Park, Erin E Grayhack, Arul Goel, Alisha F Khan, Ashten Omstead, David L Bartlett, Ajay Goel, Neda Dadgar, Patrick L Wagner, Ali H Zaidi.
      Early detection of gastrointestinal (GI) cancers remains a critical unmet clinical need, as most patients are diagnosed at advanced stages when prognosis is poor. Liquid biopsy has emerged as a transformative approach for minimally invasive cancer detection by analysing tumour-derived analytes in blood and other body fluids. Recent advances in circulating tumour DNA (ctDNA) sequencing, cell-free DNA methylation profiling, fragmentomics, extracellular vesicle and exosome characterisation, circulating tumour cell isolation and tumour-educated platelets have markedly improved sensitivity and specificity for detecting incipient malignancies. Despite these advances, sensitivity in stage I disease remains limited due to low tumour burden and minimal analyte scaling, resulting in false-negative results for small or indolent lesions. In addition, clonal haematopoiesis derived alterations can confound mutation-based assays, highlighting the need for epigenetic and multi-analyte approaches to improve specificity. Ultimately, widespread clinical adoption will require standardised, prospective trials demonstrating diagnostic accuracy and a reduction in cancer-specific mortality. Multi-analyte and machine learning-driven approaches, integrating DNA, RNA, protein and epigenomic signals, are now in late-stage clinical trials and poised for clinical translation. United States Food and Drug Administration approvals of blood-based colorectal cancer screening tests and laboratory-developed assays for hepatocellular carcinoma exemplify the translational momentum in this field. Here, we review the current landscape of liquid biopsy biomarkers for GI cancers, emphasising technological innovations, clinical performance and ongoing trials. We also discuss key challenges, including sensitivity in stage I disease, specificity amidst clonal haematopoiesis and integration with established screening paradigms. The continued evolution of assay technologies and translational research heralds a paradigm shift towards precision early detection of GI cancers, with the potential to substantially reduce mortality through earlier intervention. KEY POINTS: Liquid biopsy technologies are advancing rapidly for early detecion of GI cancers, using ctDNA, methylation profiling, fragmentomics, EVs, CTCs, and TEPs. Limited sensitivity in stage I disease remains a key barrier, largely due to low tumor burden and analyte scarcity. Clonal hematopoieses confounds mutation-based assays, emphasizing the need for epigenetic and multi-analyte strategies to improve specificity. Multi-analyte, machine-learning-driven platforms are nearing clinical translation, supported by late-stage trials and recent FDA approvals.
    Keywords:  cell‐free DNA methylation; circulating tumour DNA (ctDNA); circulating tumour cells (CTCs); early cancer detection; extracellular vesicles/exosomes; fragmentomics; gastrointestinal cancers; liquid biopsy; multi‐cancer early detection (MCED); tumour‐educated platelets (TEPs)
    DOI:  https://doi.org/10.1002/ctm2.70594
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