bims-tumhet 2026-02-08 papers

Genes Dis. 2026 May;13(3): 101832

DNA methylation heterogeneity in complex tumor microenvironment: Quantitative methods, influencing factors, and clinical implications.

Yongle Xu, Shuangyue Ma, Manyi Xu, Hongbo Zhu, Yuncong Wang, Wenbo Dong, Jing Gan, Yusen Zhao, Xinrong Li, Shuangshuang Wang, Haoyu Hu, Jiaheng He, Shangwei Ning, Hui Zhi.

5-Methylcytosine (5-mC) is the most prevalent DNA methylation modification in the human genome, and its abnormal patterns are strongly associated with tumor progression. Intratumoral and intertumoral DNA methylation heterogeneity (DNAmeH) primarily arises from cancer epigenome heterogeneity and the diverse cell compositions within the tumor microenvironment (TME). Furthermore, recent advancements in high-throughput sequencing and microarray technologies have facilitated the development of quantitative methods for measuring DNAmeH, enabling a more thorough exploration of the factors influencing it. Moreover, investigating various DNA methylation patterns at the single-cell level within the intricate TME sheds light on DNAmeH being driven by cellular heterogeneity. In addition, accumulating studies on the selection of methylation biomarkers in tissue or circulating DNA elucidate the cell specificity of DNA methylation, which is valuable for early cancer detection and personalized therapy. In this review, we elucidate the characteristics of intratumoral and intertumoral DNAmeH, considering DNAmeH differences across cancer types, among individual cells, and at allele-specific hemimethylation sites. Several metrics are summarized to quantitatively assess DNAmeH. We evaluate the factors that influence DNAmeH via these metrics, including the cell cycle phase, tumor mutational burden (TMB), cellular stemness, copy number variation (CNV), tumor subtype, tumor characteristics, tumor stage, state of tumor cells, hypoxia, and tumor purity. Finally, we highlight the deconvolution of TME cellular components and the application of predictive methylation biomarkers in cancer clinical research.

Keywords: Circulating DNA; DNAmeH; Hemimethylation; Methylation biomarkers; Tumor microenvironment

DOI: https://doi.org/10.1016/j.gendis.2025.101832

Genome Med. 2026 Feb 03.

A computational framework for sensitive tumor detection and accurate subtyping using shallow cell-free DNA methylome sequencing.

Marta Paoli, Francesca Galardi, Agostina Nardone, Chiara Biagioni, Dario Romagnoli, Samantha Di Donato, Gian Marco Franceschini, Luca Livraghi, Marta Pestrin, Giuseppina Sanna, Emanuela Risi, Ilenia Migliaccio, Erica Moretti, Luca Malorni, Laura Biganzoli, Francesca Demichelis, Matteo Benelli.

Keywords: Biomarker; Breast cancer; Circulating tumor DNA; DNA methylation; Estrogen receptor; Liquid biopsy; Methylome; Precision oncology; Tumor subtyping

DOI: https://doi.org/10.1186/s13073-026-01603-3

JAMA. 2026 Feb 02.

Opportunistic Salpingectomy for Prevention of Tubo-Ovarian Carcinoma: The European Society of Gynaecological Oncology Consensus Statements.

Jurgen M Piek, Jolijn Schauwaert, Laura Burney Ellis, Ignacio Zapardiel, François Planchamp, Kata Koblos, Joanna Kacperczyk-Bartnik, Sarah J Bowden, Houssein El Hajj, Mihaela Grigore, Miranda P Steenbeek, Nicolò Bizzarri, Maria Kyrgiou, Murat Gültekin.

Importance: The fallopian tube epithelium has been demonstrated to be an important source of tubo-ovarian carcinoma. Therefore, removal of the fallopian tubes during unrelated pelvic or abdominal surgery (opportunistic salpingectomy) can potentially lower future ovarian cancer risk.
Objectives: To assess current evidence on the efficacy, risks, and long-term outcomes of opportunistic salpingectomy and to develop consensus statements for the European Society of Gynaecological Oncology.
Evidence Review: An international working group of 14 individuals including a patient representative was formed to develop consensus statements on opportunistic salpingectomy. The MEDLINE database was used to conduct a literature review of English-language studies from January 1, 2000, through March 1, 2025, evaluating opportunistic salpingectomy for reduction of tubo-ovarian carcinoma, complication rates, additional surgical time, and impact on ovarian function. Statements were subsequently drafted collaboratively based on the review of the literature and adapted in an iterative process in conference call meetings with opportunity for anonymous and nonanonymous feedback. The anonymous voting was binary (agree/disagree) for each potential statement. Final statements reached consensus with more than 75% agreement.
Findings: In the literature review, 230 studies were identified, of which 129 were deemed relevant to consensus statement development. Consensus was achieved on 18 statements, with grades of recommendation ranging from B to D and levels of evidence from II to V. Opportunistic salpingectomy is significantly associated with a lower risk of subsequent tubo-ovarian carcinoma, with no adverse short-term impact on ovarian function. The procedure appears safe across surgical approaches, with little additional operative time. Existing evidence does not indicate harm to ovarian function or premature menopause, although long-term evidence is not available. Salpingectomy is feasible during both gynecological and nongynecological procedures and should be considered in women undergoing gynecological surgery and, where possible, in women undergoing selected nongynecological pelvic or abdominal surgeries.
Conclusions and Relevance: Existing evidence demonstrates that opportunistic salpingectomy is significantly associated with a lower risk of developing tubo-ovarian carcinoma. Clinicians should include this prevention intervention in preoperative counseling of eligible women.

DOI: https://doi.org/10.1001/jama.2025.24510

Methods Mol Biol. 2026 ;3015 43-54

Laser Capture Microdissection Followed by DNA Methylation Profiling.

Lu Liu, Yingchuo Hu, Chunhong Zheng, Yanyi Huang.

Laser capture microdissection (LCM) enables the precise isolation of morphologically defined cell populations, overcoming the confounding effects of tissue heterogeneity in DNA methylation analyses. However, the low DNA yield inherent to LCM-often derived from fewer than 1000 cells-challenges conventional bisulfite-based sequencing, which requires high DNA input and induces severe degradation. Here, we integrate LCM with Enzymatic Methyl-seq (EM-seq), a bisulfite-free, enzymatic conversion method that preserves DNA integrity by minimizing damage and reducing GC bias. Our optimized low-input library preparation protocols allow robust and reproducible methylation profiling from as few as 100 cells, with data quality comparable to that of bulk tissue samples. This strategy not only enables the isolation of tumor cells to uncover methylation signatures for early biomarker discovery and targeted therapies in oncology but also holds promise for advancing personalized medicine through patient-specific epigenetic profiling. Overall, our work establishes LCM-EM-seq as a scalable framework for spatially resolved, methylation-aware analyses of rare cell populations, opening new avenues for studying epigenetic heterogeneity in development and disease.

Keywords: Bisulfite-free conversion; DNA methylation profiling; Enzymatic Methyl-seq; Low-input library preparation; Spatially resolved methylation analysis

DOI: https://doi.org/10.1007/978-1-0716-5154-4_4

Cancer Discov. 2026 Feb 06. 16(2): 188-189

Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection-Letter.

Martin C Tammemägi.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1132

NPJ Precis Oncol. 2026 Feb 03.

Personalized ctDNA analysis for detection of residual disease and recurrence in surgically treated HNSCC patients.

Susanne Flach, Christodoulos Pipinikas, Tom Huberty, Axel Lechner, Clodagh Murray, Giovanni Marsico, Karen Howarth, Christoph Walz, Lukas Käsmann, Andreas Mock, Philipp Jurmeister, Kristian Unger, Sophia Stöcklein, Gizem Abaci, Nitzan Rosenfeld, Christoph A Reichel, Olivier Gires, Martin Canis, Philipp Baumeister.

Despite advances in multimodal therapy, survival in advanced head and neck squamous cell carcinoma (HNSCC) has improved only modestly. Tumor-informed circulating tumor DNA (ctDNA) assays allow early detection of molecular residual disease (MRD) and recurrence after curative treatment. We analyzed ctDNA in plasma from 76 and saliva from 54 HNSCC patients before and after curative-intent surgery, testing 656 plasma and 128 saliva samples longitudinally. High preoperative ctDNA shedding correlated with advanced pathological stage, lymph node involvement, adverse histologic features, and molecular markers including PD-1 expression and tumor mutational burden. Transcriptomic profiling showed associations between high shedding and increased proliferation, EGFR/MAPK pathway activity, and upregulation of EGFR-related invasion and metastasis genes. Plasma ctDNA detected ≥14 days post-surgery identified 91.3% of recurrences, with lead times up to 500 days before clinical confirmation. These results highlight the value of serial ctDNA monitoring for early relapse detection and potentially improved treatment guidance in HNSCC.

DOI: https://doi.org/10.1038/s41698-026-01309-0

Cell. 2026 Jan 29. pii: S0092-8674(25)01498-9. [Epub ahead of print]

Hallmarks of cancer-Then and now, and beyond.

Douglas Hanahan.

Cancer presents a remarkably instructive perturbation of mechanisms manifesting in our biology that have gone awry, eliciting a malady that is inexorably increasing in incidence and societal burden concomitant with healthier aging. The wealth of knowledge and data forthcoming from decades of cancer research can be organized into conceptually distinct but interconnected parametric dimensions that define the mechanistic foundation of the disease: aberrantly acquired functional capabilities (the hallmarks of cancer), enabling phenotypic characteristics, hallmark-conveying cells populating cancer microenvironments, and systemic interactions. Collectively, they provide a logical framework with which to illuminate the operating systems of these outlaw organs, from inception through multistage tumorigenesis to adaptive evolution. This review presents a concise synthesis of the hallmark conceptualization as it has been refined during the past 25 years, including a corollary hypothesis that mechanism-guided hallmark co-targeting could offer impactful new therapeutic strategies for treating human cancers.

DOI: https://doi.org/10.1016/j.cell.2025.12.049