bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2025–08–31
fourteen papers selected by
Sergio Marchini, Humanitas Research
  1. Comparison of current methods for genome-wide DNA methylation profiling.
  2. Whole-genome sequencing-based characterization of endometrial serous carcinoma.
  3. Beyond the Microscope: Integrating Liquid Biopsies into the Molecular Pathology Era of Endometrial Cancer.
  4. Role of circulating tumor DNA methylation in gastric cancer initiation and progression: A comprehensive review.
  5. Coordinated protein modules define DNA damage responses to carboplatin at single-cell resolution in human ovarian carcinoma models.
  6. Tumor-agnostic detection of circulating tumor DNA in patients with advanced pancreatic cancer using targeted DNA methylation sequencing and cell-free DNA fragmentomics.
  7. Evolution and co-occurrence of PI3K pathway gene mutations in endometrial carcinoma molecular subtypes at the single-cell level.
  8. Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases.
  9. What is spatial transcriptomics?
  10. Value of circulating free DNA methylation in the diagnosis of esophageal cancer: A systematic review and meta-analysis.
  11. Evaluation of cell-free DNA from papanicolaou smears and peripheral blood to detect endometrial cancer.
  12. Spatial dissimilarity analysis in single-cell transcriptomics.
  13. Toward the DNA methylation haplotype map of 11 common solid cancers.
  14. Global Hypomethylation as Minimal Residual Disease (MRD) Biomarker in Esophageal and Esophagogastric Junction Adenocarcinoma.
  1. Epigenetics Chromatin. 2025 Aug 25. 18(1): 57
    Comparison of current methods for genome-wide DNA methylation profiling.
    Ana Regina de Abreu, Joe Ibrahim, Vasileios Lemonidis, Ligia Mateiu, Guy Van Camp, Ken Op de Beeck.
       BACKGROUND: DNA methylation is an epigenetic mechanism involved in gene regulation and cellular differentiation. Accurate and comprehensive assessment of DNA methylation patterns is thus essential for understanding their role in various biological processes and disease mechanisms. Bisulfite sequencing has long been the default method for analyzing methylation marks due to its single-base resolution, but the associated DNA degradation poses a concern. Although several methods have been proposed to circumvent this issue, there is no clear consensus on which method might be better suited for specific study designs.
    RESULTS: We conducted a comparative evaluation of four DNA methylation detection approaches: whole-genome bisulfite sequencing (WGBS), Illumina methylation microarray (EPIC), enzymatic methyl-sequencing (EM-seq) and third-generation sequencing by Oxford Nanopore Technologies (ONT). DNA methylation profiles were assessed across three human genome samples derived from tissue, cell line, and whole blood. We systematically compared these methods in terms of resolution, genomic coverage, methylation calling accuracy, cost, time, and practical implementation. EM-seq showed the highest concordance with WGBS, indicating strong reliability due to their similar sequencing chemistry. ONT sequencing, while showing lower agreement with WGBS and EM-seq, captured certain loci uniquely and enabled methylation detection in challenging genomic regions. Despite a substantial overlap in CpG detection among methods, each method identified unique CpG sites, emphasizing their complementary nature.
    CONCLUSIONS: Our findings underscore the strengths and limitations of current DNA methylation detection methods. EM-seq and ONT emerge as robust alternatives to WGBS and EPIC, offering unique advantages: EM-seq delivers consistent and uniform coverage, while ONT excels in long-range methylation profiling and access to challenging genomic regions. These insights provide practical guidance for method selection based on specific experimental goals.
    Keywords:  Coverage; Cytosine; DNA methylation; Enzymatic methyl-sequencing (EM-seq); Epigenomics; Illumina EPIC array; Oxford Nanopore Technologies (ONT); Whole-genome bisulfite sequencing (WGBS)
    DOI:  https://doi.org/10.1186/s13072-025-00616-3
  2. Gynecol Oncol. 2025 Aug 22. pii: S0090-8258(25)00972-2. [Epub ahead of print]201 130-136
    Whole-genome sequencing-based characterization of endometrial serous carcinoma.
    Sarah Andres, David N Brown, Arnaud Da Cruz Paula, Carol Aghajanian, Nadeem R Abu-Rustum, Lora H Ellenson, Britta Weigelt.
       OBJECTIVE: To define the structural variants, mutational signatures, and DNA repair defects in serous endometrial carcinoma (EC) using whole-genome sequencing (WGS).
    METHODS: Ten primary untreated classic serous ECs diagnosed between 2012 and 2018 were selected. Tumor and matched normal DNAs were subjected to WGS, and sequencing data were analyzed using state-of-the-art bioinformatics methods.
    RESULTS: All serous ECs harbored TP53 somatic mutations (100 %), as well as recurrent PIK3CA (60 %), FBXW7 (40 %), PPP2R1A (30 %) mutations, CCNE1 (50 %) and AKT2 amplification (30 %). All serous ECs were homologous recombination DNA repair (HR)-proficient by HRDetect, and all but one case had dominant aging/clock- or ABOPEC-related mutational signatures. The levels of genomic instability varied, with a median fraction of genome altered (FGA) of 45 % (range 17-68 %). Seven serous ECs had high levels of copy number alterations (CNAs) (distinct CNA size ≥1Mbp, median 59; range 26-86) and three had low levels of CNAs (median 12 distinct CNA size ≥1Mbp; range 6-23). While there was no difference in age or stage of disease between patients with high versus low CNA levels, all three serous EC patients with lower CNA levels are still alive to date (68-99 months follow-up), as opposed to only one of seven serous EC patients with higher CNA levels (range 16-69 months follow-up) after 58 months of follow-up.
    CONCLUSIONS: Although serous ECs are characterized by TP53 mutations and generally high levels of CNAs, genomic features of HR-deficiency are not prominent. Larger prospective studies of the impact of chromosomal instability on outcome in serous EC patients are warranted.
    Keywords:  Copy number; Homologous recombination; Mutational signatures; Serous endometrial; Whole-genome
    DOI:  https://doi.org/10.1016/j.ygyno.2025.08.022
  3. Int J Mol Sci. 2025 Aug 19. pii: 7987. [Epub ahead of print]26(16):
    Beyond the Microscope: Integrating Liquid Biopsies into the Molecular Pathology Era of Endometrial Cancer.
    Miguel Perez, Luis Lorenzo Carvajal, Andres Wong, Robert Poppiti, Roberto Ruiz-Cordero, Amilcar A Castellano-Sánchez, Hisham F Bahmad.
      Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with a growing incidence and significant molecular heterogeneity that challenges traditional diagnostic and management paradigms. While histopathological assessment remains the gold standard for diagnosis, emerging liquid biopsy technologies provide promising non-invasive alternatives for tumor detection, molecular profiling, and disease monitoring. This review comprehensively explores the current landscape and clinical utility of liquid biopsy analytes-including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), extracellular RNAs, and exosomes-in the context of EC. We discuss the evolving role of pathologists in integrating molecular data with histomorphological features to enhance diagnostic precision, prognostic stratification, and therapeutic decision-making. Novel technologies such as methylation-based assays, tumor-informed ctDNA sequencing, and tumor-educated platelets (TEPs) are highlighted for their diagnostic accuracy and potential for early detection. Furthermore, we summarize key clinical trials and future directions aimed at validating liquid biopsy platforms for routine clinical implementation. As EC care transitions toward a precision oncology model, the integration of liquid biopsy with traditional surgical pathology offers a transformative approach to individualized and personalized patient management.
    Keywords:  cell-free DNA (cfDNA); circulating tumor DNA (ctDNA); circulating tumor cells (CTCs); endometrial cancer (EC); liquid biopsy; molecular; review
    DOI:  https://doi.org/10.3390/ijms26167987
  4. World J Gastrointest Oncol. 2025 Aug 15. 17(8): 107412
    Role of circulating tumor DNA methylation in gastric cancer initiation and progression: A comprehensive review.
    Hai-Yu Huang, Jiang Lan, Wei Zhuang.
      Circulating tumor DNA (ctDNA) is the free DNA released by tumor or circulating tumor cells, which is associated with many tumor characteristics and can be used as a biomarker for early screening, monitoring, prognosis, and prediction of therapeutic response in patients with cancer. The field of gastric cancer is very attractive because there are no high-quality screening, monitoring, or prediction methods. Gastric cancer is characterized by great tumor heterogeneity, great differences in genetic and epigenetic characteristics among different subgroups of gastric cancer, and high sensitivity and specificity of methylated ctDNA, which is conducive to the identification of tumor genotypes and the formulation of accurate diagnostic and treatment strategies. In addition, many studies have confirmed that methylated DNA has unique advantages in predicting treatment response, adjuvant therapy, and drug resistance and can be used to increase the efficacy of chemotherapy regimens, improve the chemotherapy response of patients in the future, and even treat multidrug resistance. However, methylated ctDNA also faces many problems, such as low sensitivity and specificity in a single target, limited association between some gastric cancer subtypes and ctDNA, risk of off-target effects, and lack of large-sample and high-quality clinical research evidence. This review mainly summarizes the current research on the DNA methylation of circulating gastric cancer tumors and links these findings with the early screening of gastric cancer, recurrence monitoring, and potential treatment opportunities. With the advancement of technology and the deepening of cross-research between doctors and professionals, ctDNA detection will reveal more disease information and become an important basis for the field of gastric cancer and precision medicine treatment.
    Keywords:  Biomarkers; Circulating tumor DNA; DNA methylation; Early screening; Gastric neoplasms
    DOI:  https://doi.org/10.4251/wjgo.v17.i8.107412
  5. Cell Rep Med. 2025 Aug 19. pii: S2666-3791(25)00368-4. [Epub ahead of print] 102295
    Coordinated protein modules define DNA damage responses to carboplatin at single-cell resolution in human ovarian carcinoma models.
    Jacob S Bedia, Antonio Delgado-Gonzalez, Ying-Wen Huang, Veronica D Gonzalez, Ionut-Gabriel Funingana, Zainab Rahil, Alyssa Mike, Alexis Lowber, Maria Vias, Alan Ashworth, James D Brenton, Wendy J Fantl.
      Tubo-ovarian high-grade serous carcinoma (HGSC), the most lethal gynecologic malignancy, initially responds to platinum-based chemotherapy, but due to frequent defects in the DNA damage response (DDR), most tumors develop resistance. The molecular mechanisms underlying clinical platinum resistance remain poorly defined with no biomarkers or targeted therapies to improve outcomes. Here, applying mass cytometry, we quantify phosphorylation and abundance of DDR proteins in carboplatin-treated HGSC cell line models. Despite similar levels of intranuclear platinum, a proxy for carboplatin uptake, cells follow divergent fates, reflecting DDR heterogeneity. Unsupervised analysis reveals a continuum of DDR states, and matrix factorization identifies eight protein modules. The activity of one module, containing canonical DDR proteins, increases in carboplatin-sensitive cells. Resistant cells engage a broader DDR protein module. These findings demonstrate the ability of single-cell proteomics to identify functional DDR states and reveal a DDR sensitivity module as a promising biomarker for clinical stratification and therapeutic decisions in HGSC.
    Keywords:  CIOV1; CIOV2; CIOV3; DNA damage response; UWB1.289; Uniform ManifoldApproximation and Projection/UMAP; carboplatin resistance; mass cytometry/CyTOF; non-negative matrix factorization; partition-based graph abstraction; single cells; tubo-ovarian high grade carcinoma
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102295
  6. Mol Oncol. 2025 Aug 26.
    Tumor-agnostic detection of circulating tumor DNA in patients with advanced pancreatic cancer using targeted DNA methylation sequencing and cell-free DNA fragmentomics.
    Morten Lapin, Kjersti Tjensvoll, Karin Hestnes Edland, Satu Oltedal, Herish Garresori, Bjørnar Gilje, Saga Ekedal, Trygve Eftestøl, Jan Terje Kvaløy, Filip Janku, Oddmund Nordgård.
      We investigated whether DNA methylation and cell-free DNA (cfDNA) fragmentation patterns can improve circulating tumor DNA (ctDNA) detection in advanced pancreatic cancer. In a cohort of 33 patients, ctDNA detection was performed in a tumor-agnostic fashion using DNA methylation, cfDNA fragment lengths, and 4-mer 5' end motifs. Machine learning models estimating ctDNA levels were built for each individual detection method and their combination. All models significantly differentiated ctDNA levels in patients from healthy individuals (P < 0.001). Using the highest estimated levels in healthy volunteers as cutoffs, ctDNA was detected in 79%, 67%, 67%, and 55% of patients using methylation, fragment length, end motifs, and the combined model, respectively. Univariable Cox regression showed that all ctDNA level estimates were associated with increased hazard ratios (HR, all P < 0.001) for progression-free survival (PFS) and overall survival (OS). Multivariable Cox regression confirmed ctDNA levels as an independent predictor of PFS (HR = 1.9, P < 0.001) and OS (HR = 2.7, P < 0.001). Our findings suggest that machine learning models based on DNA methylation, cfDNA fragment lengths, and cfDNA end motifs can estimate ctDNA levels and predict clinical outcomes in advanced pancreatic cancer.
    Keywords:  DNA methylation; cfDNA; cfDNA fragmentomics; ctDNA; machine learning; pancreatic cancer
    DOI:  https://doi.org/10.1002/1878-0261.70116
  7. Clin Cancer Res. 2025 Aug 20.
    Evolution and co-occurrence of PI3K pathway gene mutations in endometrial carcinoma molecular subtypes at the single-cell level.
    Arnaud Da Cruz Paula, Yingjie Zhu, David N Brown, Shirin Issa Bhaloo, Fresia Pareja, Timothy J Hoang, Hunter Green, Thais Basili, Higinio Dopeso, Pier Selenica, Edaise M da Silva, Nadeem Riaz, Sarat Chandarlapaty, Nadeem R Abu-Rustum, Jorge S Reis-Filho, Britta Weigelt.
       PURPOSE: The PI3K pathway is altered in >85% of endometrioid endometrial carcinomas (EECs), with multiple mutations commonly co-occurring. Yet, the therapeutic effects of single-agent PI3K pathway inhibitors have been limited. We used single-cell sequencing to determine whether co-occurring PTEN, PIK3CA, and/or PIK3R1 somatic mutations in EECs stratified by molecular subtype originated through convergent or linear evolution.
    METHODS: Banked frozen EECs with co-occurring PI3K pathway mutations of no specific molecular profile (NSMP; n=5), mismatch repair-deficient (MMRd;n=3), and POLE (n=3) subtype were selected for single-nucleus DNA sequencing targeting hotspot variants of 64 cancer-related genes and the PTEN, PIK3R1 and PIK3CA coding sequences. EEC cell lines and non-malignant samples were used to define error rates and filter false-positive calls.
    RESULTS: Single-nucleus analyses (n=50,009 cells) revealed that in NSMP EECs, the co-occurring PIK3CA, PIK3R1, and/or PTEN mutations affected nearly all cells through linear evolution. MMRd EECs displayed higher levels of genetic heterogeneity, harboring PI3K pathway gene mutations in subsets of cells ranging from 3.9%-96%. POLE EECs had the highest level of clonal diversity and harbored multiple minor subclonal structures in all cases, through convergent evolution. We found a clear distinction between nearly clonal PI3K pathway gene alterations (>95%) and multiple minor, mutually-exclusive subclones only affecting 1.4%-27% of the tumor cells sequenced.
    CONCLUSIONS: Our exploratory, hypothesis-generating analysis suggest that PI3K pathway alterations evolve distinctly in MMRd/POLE compared to NSMP EECs, which may have therapeutic consequences. Further studies on the signaling output and PI3K pathway inhibitor response in EECs with subclonal PI3K pathway alterations are warranted.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-1237
  8. Proc Natl Acad Sci U S A. 2025 Aug 26. 122(34): e2426890122
    Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases.
    PLATO-VTE Study Group
      Multiple case-controlled studies have shown that analyzing fragmentation patterns in plasma cell-free DNA (cfDNA) can distinguish individuals with cancer from healthy controls. However, there have been few studies that investigate various types of cfDNA fragmentomics patterns in individuals with other diseases. We therefore developed a comprehensive statistic, called fragmentation signatures, that integrates the distributions of fragment positioning, fragment length, and fragment end-motifs in cfDNA. We found that individuals with venous thromboembolism, systemic lupus erythematosus, dermatomyositis, or scleroderma have cfDNA fragmentation signatures that closely resemble those found in individuals with advanced cancers. Furthermore, these signatures were highly correlated with increases in inflammatory markers in the blood. We demonstrate that these similarities in fragmentation signatures lead to high rates of false positives in individuals with autoimmune or vascular disease when evaluated using conventional binary classification approaches for multicancer earlier detection (MCED). To address this issue, we introduced a multiclass approach for MCED that integrates fragmentation signatures with protein biomarkers and achieves improved specificity in individuals with autoimmune or vascular disease while maintaining high sensitivity. Though these data put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, they also offer ways to improve the interpretability of such tests. Moreover, we expect these results will lead to a better understanding of the process-most likely inflammatory-from which abnormal fragmentation signatures are derived.
    Keywords:  autoimmune diseases; cancer screening; cell-free DNA; fragmentomics; rheumatology
    DOI:  https://doi.org/10.1073/pnas.2426890122
  9. Arch Dis Child Educ Pract Ed. 2025 Aug 27. pii: edpract-2025-328924. [Epub ahead of print]
    What is spatial transcriptomics?
    Anne van Kuijk.
      
    Keywords:  Genetics; Paediatrics; Technology
    DOI:  https://doi.org/10.1136/archdischild-2025-328924
  10. Oncol Lett. 2025 Oct;30(4): 478
    Value of circulating free DNA methylation in the diagnosis of esophageal cancer: A systematic review and meta-analysis.
    Chenxiao Ma, Yixian Wang, Zuopan Ding, Xingxing Liang, Meng Yuan, Xuan Liu, Qiong Li, Hongbo Lv, Na Qiao, Xin Liu.
      Liquid biopsy using circulating biomarkers has shown growing potential in cancer detection. The aim of the present study was to assess the application value of detecting the methylation level of circulating free (cf)DNA in the identification and diagnosis of esophageal cancer (EC), to lay a scientific foundation for its clinical application, and to provide statistically significant references for the detection process. A total of two researchers independently performed a comprehensive search of the PubMed, Web of Science, Cochrane Library, Embase and Scopus databases to identify all relevant studies on cfDNA in EC diagnosis as of July 25, 2024. A meta-analysis was performed using MetaDiSc 1.4, Stata 16.0 and RevMan 5.4 software. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic rate (DOR) and area under the curve (AUC) values were determined. According to inclusion and exclusion criteria, a total of 14 studies with a total of 3,936 patients were included in the analysis. The pooled sensitivity and specificity, and PLR, NLR, DOR and AUC of cfDNA methylation in the diagnosis of EC were 0.83 [95% confidence interval (CI), 0.75-0.89], 0.98 (95% CI, 0.95-0.99), 34.57 (95% CI, 18.04-63.44), 0.18 (95% CI, 0.12-0.25), 197.25 (95% CI, 104.53-372.20) and 0.98 (95% CI, 0.96-0.99), respectively. In conclusion, cfDNA methylation demonstrates high diagnostic accuracy for early-stage EC and may serve as a promising non-invasive screening tool.
    Keywords:  circulating free DNA; diagnosis; esophageal cancer; meta-analysis
    DOI:  https://doi.org/10.3892/ol.2025.15225
  11. Front Oncol. 2025 ;15 1570938
    Evaluation of cell-free DNA from papanicolaou smears and peripheral blood to detect endometrial cancer.
    Yao Wang, Jia-Xin Yang, Mei Yu.
       Objective: This study aimed to identify tumor-derived DNA in Papanicolaou (Pap) smears and plasma specimens from patients with endometrial cancer or endometrial intraepithelial neoplasia (EC/EIN).
    Methods: Tumor tissue, peripheral blood, and Pap smear samples were collected from 84 patients with EC and EIN. Somatic mutations in tumor specimens were analyzed using targeted exome sequencing with a 363-cancer-related gene panel. Circulating single-molecule amplification and resequencing technology (cSMART) was used to evaluate somatic mutations in Pap smear and plasma circulating cell-free DNA (cfDNA).
    Results: Higher pathological grades and lymph node metastases in EC were associated with elevated plasma cfDNA concentrations (p < 0.05 for both). Mutations corresponding to tissue samples were identified in 42.9% of plasma cfDNA and 77.4% of Pap smear cfDNA, with Pap smears demonstrating a higher detection rate (p < 0.05). In patients with EC, the detection rate of consistent mutations in cfDNA from peripheral blood was significantly elevated in those with higher pathological grades, lymphovascular space involvement, and lymph node metastasis (p < 0.05). The detection rate of consistent mutations in cfDNA from Pap smears was significantly higher in the EC group (p < 0.001).
    Conclusion: Multi-gene panels can detect tumor-derived DNA in cfDNA from both blood and Pap smears of patients with EC, with Pap smear cfDNA potentially offering higher efficacy for liquid biopsies in EC. This approach could complement tissue biopsies for early diagnosis and risk stratification, warranting further investigation into the clinical utility of liquid biopsies for EC management.
    Keywords:  cSMART; cell-free DNA; endometrial cancer; endometrial intraepithelial neoplasia; liquid biopsy
    DOI:  https://doi.org/10.3389/fonc.2025.1570938
  12. Cell Rep Methods. 2025 Aug 12. pii: S2667-2375(25)00177-8. [Epub ahead of print] 101141
    Spatial dissimilarity analysis in single-cell transcriptomics.
    Quan Shi, Karsten Kristiansen.
      We develop the spatial dissimilarity method to uncover complex bivariate relationships in single-cell and spatial transcriptomics data, addressing challenges such as alternative splicing and allele-specific gene expression. Applying this method to detect alternative splicing in neurons demonstrates improved accuracy and sensitivity compared to existing tools, notably identifying neuron subtypes. In tumor cells, spatial dissimilarity analysis reveals somatic variants that emerge during tumor progression, validated through whole-exome sequencing. These findings highlight how allele-specific genetic variants contribute to the subclone architecture of cancer cells, offering insights into cellular heterogeneity. Applied on a human cell atlas, we uncover numerous cases of allele-specific expression of genes in normal cells. We provide a software package for spatial dissimilarity analysis to enable enhanced understanding of cellular complexity and gene expression dynamics under homeostatic conditions and during states of transitions.
    Keywords:  CP: computational biology; CP: systems biology; allele-specific gene expression; alternative splicing; cancer genomics; lineage trajectory; single-cell RNA-seq; single-cell genomics; somatic mosaicism; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101141
  13. Cell Rep. 2025 Aug 23. pii: S2211-1247(25)00968-4. [Epub ahead of print]44(9): 116197
    Toward the DNA methylation haplotype map of 11 common solid cancers.
    Zhiqiang Zhang, Yuyang Hong, Shirong Zhang, Xin Zhu, Leiqin Liu, Xiqi Liao, Hongcang Gu, Hai Fang, Jiantao Shi.
      In heterogeneous tumors, adjacent CpG sites form methylation haplotype blocks (MHBs), genomic regions where methylation status reflects local epigenetic concordance. While MHBs have been implicated in gene dysregulation, their pan-cancer dynamics and clinical relevance remain unclear. We profiled 110 primary tumors across 11 common solid cancer types, identifying 81,567 MHBs. These MHBs exhibit high cancer-type specificity, with enrichment in regulatory elements. Integrative bulk and single-cell analyses reveal that MHBs associate with gene expression independently of mean methylation changes. Moreover, pan-cancer prioritization of MHB-associated differentially expressed genes highlights their roles in oncogenic pathways such as the G2/M checkpoint, MYC targets, and E2F signaling. Inter-tumor heterogeneity links MHB discordance to driver mutations and inflammatory pathways. Finally, we demonstrate that MHBs serve as effective biomarkers for cancer detection, performing competitively to existing methods. This resource positions MHBs as multimodal epigenetic regulators, bridging tumor heterogeneity, transcriptional control, and liquid biopsy diagnostics.
    Keywords:  CP: Cancer; CP: Molecular biology; DNA methylation; MHB; cancer detection; methylation haplotype block; pan-cancer; transcriptional regulation; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116197
  14. Cancers (Basel). 2025 Aug 15. pii: 2668. [Epub ahead of print]17(16):
    Global Hypomethylation as Minimal Residual Disease (MRD) Biomarker in Esophageal and Esophagogastric Junction Adenocarcinoma.
    Elisa Boldrin, Maria Assunta Piano, Alice Volpato, Rita Alfieri, Monica Franco, Tiziana Morbin, Annalisa Masier, Stefano Realdon, Genny Mattara, Giovanna Magni, Antonio Rosato, Pierluigi Pilati, Alberto Fantin, Matteo Curtarello.
      Background/Objectives: Esophageal and esophagogastric junction adenocarcinoma (EADC-EGJA), which mainly develops from Barrett's esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), has a poor prognosis and several unmet clinical needs, among which is the detection of minimal residual disease (MRD) after endoscopic/surgical resection. Long interspersed nuclear element-1 (LINE-1), a surrogate marker of global methylation, is considered an emerging biomarker for MRD monitoring. The aim of this study was to determine, by LINE-1 methylation analysis, at which carcinogenesis step global methylation is affected and whether this biomarker could be followed in longitudinal to monitor the disease behavior post-surgery. Methods: Cell-free DNA of 90 patients with non-dysplastic Barrett's esophagus (NDBE), HGD/early EADC-EGJA, or locally advanced/advanced EADC-EGJA were analyzed for LINE-1 methylation, by Methylation-Sensitive Restriction Enzyme droplet digital PCR (MSRE-ddPCR). Twenty-six patients were longitudinally studied by repetitive blood sampling. Results: Global hypomethylation increased during carcinogenesis, with significant difference between locally advanced/advanced EADC-EGJA and NDBE patients (p = 0.028). Longitudinal cases confirmed the rareness of hypomethylation in NDBE cases. The majority of HGD/early EADC-EGJA and locally advanced/advanced EADC-EGJA patients showed methylation changes after resection according to clinical status. Conclusions: This study suggests that global hypomethylation occurs just prior to cancer invasiveness and that it is a promising biomarker to monitor MRD.
    Keywords:  Barrett’s esophagus (BE); Methylation-Sensitive Restriction Enzyme droplet digital PCR (MSRE-ddPCR); esophageal adenocarcinoma (EADC); esophagogastric junction adenocarcinoma (EGJA); global hypomethylation; liquid biopsy; minimal residual disease (MRD)
    DOI:  https://doi.org/10.3390/cancers17162668
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