bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2025–12–21
ten papers selected by
Sergio Marchini, Humanitas Research
  1. Improved circulating tumor DNA profiling by simultaneous extraction of DNA methylation and copy number information from methylated DNA sequencing data.
  2. Broad Utility of Ultrasensitive Analysis of ctDNA Dynamics across Solid Tumors Treated with Immunotherapy.
  3. Comprehensive benchmarking of methods for mutation calling in circulating tumor DNA.
  4. Clinical performance of tumor-informed versus tumor-agnostic ctDNA assays for colorectal cancer recurrence: A systematic review and diagnostic accuracy meta-analysis.
  5. Circulating tumor DNA as a biomarker in early phase clinical trials.
  6. Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions.
  7. Fibroblast-like cells in mesothelioma can derive from tumor cells.
  8. Challenges in the future of cancer screening.
  9. Plasma cell-free DNA methylation-based prognosis in metastatic castrate-resistant prostate cancer.
  10. The 'vulnerability code': Is cell identity the architect of its own decay?
  1. NPJ Precis Oncol. 2025 Dec 15.
    Improved circulating tumor DNA profiling by simultaneous extraction of DNA methylation and copy number information from methylated DNA sequencing data.
    Daan M Hazelaar, Ruben G Boers, Joachim B Boers, Vanja de Weerd, Jean Helmijr, Maurice Phm Jansen, Henk Mw Verheul, Cornelis Verhoef, Joost Gribnau, John Wm Martens, Stavros Makrodimitris, Saskia M Wilting.
      Cell-free DNA (cfDNA) analysis offers a powerful, minimally invasive approach to improve cancer care by measuring tumor-specific genomic and epigenetic alterations. Here, we demonstrate the versatility of MeD-seq, a methylation-dependent sequencing assay, for comprehensive cfDNA analysis, including DNA methylation profiling, chromosomal copy number (CN) alterations, and tumor fraction (TF) estimation. MeD-seq-derived CN profiles and TF estimates from 38 colorectal cancer patients with liver metastases (CRLM) and 5 ovarian cancer patients were highly comparable to shallow whole-genome sequencing (sWGS), validating our approach. For 120 CRLM patients, we used MeD-seq CN and TF information in an improved differential methylation model, which detected additional significantly Differentially Methylated Regions (DMRs) correlating with TF estimates. Using the identified DMR sets, we were subsequently able to distinguish healthy blood donors from CRLM patients with low amounts of circulating tumor DNA (ctDNA) as well. These findings establish MeD-seq as an affordable platform for tumor-agnostic detection of cancer-specific signals in plasma. This methodological framework provides a foundation for clinical applications requiring sensitive ctDNA detection from limited sample material, including treatment response assessment and minimal residual disease monitoring.
    DOI:  https://doi.org/10.1038/s41698-025-01237-5
  2. Clin Cancer Res. 2025 Dec 16. OF1-OF17
    Broad Utility of Ultrasensitive Analysis of ctDNA Dynamics across Solid Tumors Treated with Immunotherapy.
    Elena Garralda, Charles Abbott, Alma Calahorro, Oriol Mirallas, Jason Pugh, Ana Belén Moreno-Cárdenas, Kathleen Keough, Vladimir Galvao, Guzman Alonso, Armando Mel Olano, María Vieito Villar, Arjun Oberoi, Julia Lostes Bardaji, Alberto Hernando-Calvo, Irene Braña, Giulia Pretelli, Belen Ortega, Carlota Arenillas, Natalia Czerniak, Fábio C P Navarro, Bailiang Li, Rachel Marty Pyke, Neeraja Ravi, Christina Zatse, Francesco Grussu, Marta Sanz, Cristina Viaplana, Kira Raskina, Jose Jimenez, Roberta Fasani, Patricia Casbas-Hernandez, Ezoglin Oflazoglu, Darren Hodgson, Jorge Reis-Filho, Enriqueta Felip, Elena Élez, Eva Muñoz, Rodrigo Dienstmann, Josep Tabernero, Raquel Lopez-Perez, Paolo Nuciforo, Richard O Chen, Sean M Boyle, Rodrigo A Toledo.
       PURPOSE: Prior studies have suggested the biomarker potential of plasma-derived ctDNA in patients with cancer treated with immune checkpoint inhibitors. This study investigated the ability of ctDNA to predict progression-free and overall survival in a cohort of patients with advanced cancer treated with immunotherapies.
    EXPERIMENTAL DESIGN: In order to characterize the potential role of ultrasensitive ctDNA detection in the management of these patients, we have performed tumor whole-genome sequencing-informed, ultrasensitive ctDNA analysis-tracking approximately 1,800 tumor-specific mutations per patient-in a retrospective cohort (n = 136) and a prospective validation cohort (n = 66) across 24 cancer types treated with immune checkpoint inhibitors alone or in combination with bispecific antibodies or immune cell engagers.
    RESULTS: Analyzing 1,455 longitudinal samples, we found that ctDNA molecular response measured as early as 3 weeks after treatment initiation correlated with improved progression-free and overall survival, whereas ctDNA clearance at any time strongly correlated with radiologic response and prolonged survival. Additionally, ctDNA dynamics distinguished true progression from pseudoprogression and predicted outcomes in patients receiving continued immunotherapy beyond initial progression.
    CONCLUSIONS: This study highlights the broader applicability of ultrasensitive ctDNA as a biomarker across cancer types and immunotherapy modalities.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-2312
  3. Nat Commun. 2025 Dec 18.
    Comprehensive benchmarking of methods for mutation calling in circulating tumor DNA.
    Hanaé Carrié, Ngak Leng Sim, Pui Mun Wong, Anna Gan, Yi Ting Lau, Polly Poon, Saranya Thangaraju, Iain Tan, Yoon Sim Yap, Kiran Krishnamachari, Limsoon Wong, Anders Skanderup.
      Detection of somatic mutations in cell-free DNA (cfDNA) is challenging due to low variant allele frequencies and extensive DNA degradation. Here we develop a benchmarking strategy using longitudinal patient-matched cfDNA samples from individuals with colorectal and breast cancer. Samples with high and ultra-low levels of tumor-derived DNA are combined into controlled dilution series that preserve the properties of authentic cell-free DNA, including each patient's germline and blood-cell mutation backgrounds. Using deep whole-genome (150x) and exome (2,000x) sequencing, we define a reference set of ~37,000 single nucleotide variants and ~58,000 indels to benchmark nine somatic variant callers across varying ctDNA levels and sequencing depths. We also explore machine learning-based tuning of individual callers and identify features that improve accuracy in cfDNA. This benchmarking resource clarifies the detection limits of current approaches and provides practical guidance for selecting somatic variant calling methods in liquid biopsy applications.
    DOI:  https://doi.org/10.1038/s41467-025-67842-x
  4. Cancer Treat Rev. 2025 Dec 07. pii: S0305-7372(25)00188-4. [Epub ahead of print]142 103066
    Clinical performance of tumor-informed versus tumor-agnostic ctDNA assays for colorectal cancer recurrence: A systematic review and diagnostic accuracy meta-analysis.
    Daniel G Camblor, Belén Martínez-Castedo, Jorge Martín-Arana, Francisco Gimeno-Valiente, Blanca García-Micó, Francisco Martínez-Picó, Víctor Seguí, Miguel García-Bartolomé, Diego González, Alejandro Guimera, Marisol Huerta, Susana Roselló, Valentina Gambardella, Desamparados Roda, Leontios Pappas, Aparna Parikh, Juan Antonio Carbonell-Asins, Andrés Cervantes, Noelia Tarazona.
      In patients with early-stage colorectal cancer (CRC), circulating tumor DNA (ctDNA) testing is increasingly used to detect minimal residual disease (MRD) after curative-intent surgery. This information can guide decisions on adjuvant chemotherapy and surveillance. Two main approaches exist, tumor-informed (TI) and tumor-agnostic (TA), however, their diagnostic accuracy in clinical practice remains unclear. We conducted a bivariate diagnostic meta-analysis to compare sensitivity and specificity of TI versus TA ctDNA assays for detecting recurrence in patients with resected CRC. Subgroup analyses were performed based on landmark versus serial sampling strategies. In the serial-sampling setting, TI assays demonstrated markedly higher sensitivity than TA assays (0.88 vs. 0.59; p = 0.001), with no significant differences in false-positive rates. The landmark analyses did not show statistically significant differences between approaches. The results underscore the importance of sampling strategy when selecting a ctDNA test. When longitudinal monitoring is feasible, TI assays provide the most reliable detection of recurrence. This meta-analysis supports tailoring ctDNA testing to the clinical context, prioritizing TI approaches for serial surveillance to better guide adjuvant decision-making and improve patient outcomes.
    Keywords:  Circulating tumor DNA; Colorectal cancer; Diagnostic accuracy; False positive rate; Sensitivity; Tumor-agnostic; Tumor-informed
    DOI:  https://doi.org/10.1016/j.ctrv.2025.103066
  5. Cancer Cell. 2025 Dec 18. pii: S1535-6108(25)00504-5. [Epub ahead of print]
    Circulating tumor DNA as a biomarker in early phase clinical trials.
    Harold N Tan, Mitchell J Elliott, Ian M Silverman, Lillian L Siu, Timothy A Yap.
      The clinical development of novel cancer therapeutics is rapidly evolving with the integration of molecular biomarkers to advance precision medicine. Circulating tumor DNA (ctDNA) represents a versatile tool to detect targetable alterations, predict therapeutic response, monitor tumor evolution, and inform pharmacokinetic and pharmacodynamic effects. This could accelerate early phase drug development and deepen our understanding of biological drivers of response and resistance. Herein, we highlight current applications and future opportunities for ctDNA as a multi-utility biomarker in early phase clinical trials.
    DOI:  https://doi.org/10.1016/j.ccell.2025.11.011
  6. Cancer Res. 2025 Dec 18.
    Integrated Spatial Analysis Reveals the Molecular Landscape of Ovarian Precancerous Lesions.
    Tu-Yung Chang, Yen-Wei Chien, Szu-Hua Chen, Annelise Sokolow, Yeh Wang, Brant G Wang, Tricia A Numan, M Herman Chui, Rebecca L Stone, Thomas R Pisanic, Nickolas Papadopoulos, Tian-Li Wang, Christopher Douville, Leslie Cope, Ie-Ming Shih.
      Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. Here, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinicopathological features in 166 ovarian precancerous lesions. Four pre-cancerous transcriptomic subtypes were identified: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline-BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immune-regulatory gene expression, and histological features. Notably, the immunoreactive subtype upregulated immune-regulatory genes, exhibited chronic inflammation, and was enriched in cases with germline-BRCA1/2 mutations, deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double "two-hit" involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial-mesenchymal transition, and extracellular matrix remodeling. In summary, these results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive pre-cancerous lesions.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3189
  7. Cell Death Differ. 2025 Dec 16.
    Fibroblast-like cells in mesothelioma can derive from tumor cells.
    Jose M Garcia-Manteiga, Eltjona Rrapaj, Francesca Caprioglio, Francesco De Marchis, Andrea Lamarca, Liam S Colley, Angelo Carretta, Daniela Finocchiaro, Francesca Mercalli, Annamaria Molinario, Gianluigi Arrigoni, Renzo Boldorini, Massimo P Crippa, Rosanna Mezzapelle, Marco E Bianchi.
      Pleural mesothelioma (PM) is an aggressive cancer that originates from mesothelial cells lining the pleura. To identify the different cell types in mesothelioma and their relationships, we performed single-cell RNAseq analyses of non-malignant pleura biopsies, PM biopsies and PM patient-derived organoids. Gene expression profiles of mesothelial and mesothelioma cells are very similar, suggesting that mesothelioma cells retain most properties of mesothelial cells. Surprisingly, in PM patient-derived organoids mesothelioma cells can acquire a fibroblast-like gene expression profile. Indeed, in most of the original PM biopsies a fraction of cells within the cluster of cancer-associated fibroblasts (CAFs) appear derived from tumor cells, with which they share the same genomic rearrangements. We confirmed by immunohistochemistry, and thus at the protein level, that cancer-derived fibroblast-like cells (CDFs) express smooth muscle actin, as most CAFs do, but have lost the same tumor suppressor proteins as the cognate mesothelioma cells. We propose that mesothelioma cells can become CDFs because they retain the ability of mesothelial cells to differentiate into fibroblasts. CDFs are thus tumor cells with fibroblast-like gene expression associated to tumors, and fulfil the definition of CAFs. CAFs generally support tumor progression, and in most tumors derive from resident fibroblasts or circulating mesenchymal cells. Our finding that a subset of CAFs derive from tumor cells, at least in mesothelioma, challenges current understanding of CAF origin. We suggest that interfering with the mesothelioma-to-CAF transition might offer an avenue to moderate tumor progression and resistance to therapy.
    DOI:  https://doi.org/10.1038/s41418-025-01639-9
  8. Int J Cancer. 2025 Dec 16.
    Challenges in the future of cancer screening.
    Future of Cancer Screening Working Group
      The purpose of cancer screening is to reduce mortality, and ideally incidence, from the cancer screened for. Until recently, cancer screening has been offered to all persons in pre-defined sex- and age-groups. The exception is lung screening which is targeted to high-risk individuals. Evidence for effect of screening on cancer-specific mortality is available for cancer of the cervix, breast, colorectal, lung, and prostate, and on cancer-specific incidence for cervix and colorectal cancer. With more effective molecular and computational tools, the current paradigm of cancer screening will change. Manual reading of images and pathology in mammography, cytology, colposcopy, colonoscopy, and CT scan will be complemented or replaced by AI-interpretation. Risk stratification will diversify screening intensity, for instance in breast screening where modelling and randomized controlled trials are underway. Blood-based screening tests might allow for simultaneous early detection of several types of cancer. Furthermore, prediction models based on life trajectories in health and other data will enhance risk stratification, potentially dividing the population into groups with no need of screening, with need of simple or advanced screening, with need of surveillance or even diagnostics. In public health care systems, these developments must be closely monitored. Before replacing an existing program, evidence for non-inferiority in reducing cancer-specific mortality should be ensured. Benefits must outweigh harms, and citizens should have confidence in new screening schemes. With the pressure on health care resources, screening should continue in organized and monitored programs. Taking these conditions into account, the new screening tools will potentially enable improved cancer control.
    Keywords:  cancer; evidence; screening
    DOI:  https://doi.org/10.1002/ijc.70286
  9. NPJ Precis Oncol. 2025 Dec 13.
    Plasma cell-free DNA methylation-based prognosis in metastatic castrate-resistant prostate cancer.
    Jodie Wong, Yijun Tian, Manishkumar S Patel, Kapil Avasthi, Claire Hanson, Matt Larsen, Enos Ampaw, Rebekah Gutowski, Muhammad Z H Fadlullah, Joseph Finkelstein, Aik Choon Tan, Jong Park, Brandon J Manley, Chiang-Ching Huang, Manish Kohli, Liang Wang.
      Molecular prognostication in metastatic castration-resistant prostate cancer (mCRPC) remains a challenge due to the lack of validated biomarkers. This study developed a plasma cell-free DNA (cfDNA) methylation-based prognostic model in mCRPC. Targeted cfDNA methylation sequencing in 96 prostate cancer patients across different states of cancer progression revealed 77 methylation haplotype blocks (MHBs) differentially methylated from organ-confined prostate cancer to mCRPC states. Among these 77 MHBs, the top 20 MHBs were associated with mCRPC overall survival and most MHB methylation levels positively correlated with predicted circulating tumor DNA (ctDNA) fraction. By integrating the MHB-based risk score with currently available prognostic clinical variables and ctDNA fraction, a prognostic nomogram was developed which showed high predictive performance for mCRPC survival (AUC = 0.99 for 6 months, AUC = 0.84 for 1 year, and AUC = 0.82 for 2 years). These findings demonstrate potential of cfDNA methylation as a molecular biology-driven biomarker for mCRPC prognosis.
    DOI:  https://doi.org/10.1038/s41698-025-01232-w
  10. Clin Transl Med. 2025 Dec;15(12): e70555
    The 'vulnerability code': Is cell identity the architect of its own decay?
    Dongsheng Bai, Zhenkun Cao, Chenxu Zhu.
      
    DOI:  https://doi.org/10.1002/ctm2.70555
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