bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–11–16
ten papers selected by
Lara Paracchini, Humanitas Research
  1. Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets.
  2. Preferences of BRCA mutation carriers for attributes of risk-reducing surgical options for breast and ovarian cancer.
  3. Somatic mutations at scale.
  4. At the brink of a paradigm shift in early cancer detection: Insights and directions for the modeling community.
  5. Cell-Free DNA Hypermethylation in Patients with Acute Pancreatitis.
  6. Characterization of the cell-free DNA released by tumor organoids derived from colorectal cancer patients.
  7. Library Preparation for Genome-Wide DNA Methylation Profiling.
  8. Open chromatin-guided interpretable machine learning reveals cancer-specific chromatin features in cell-free DNA.
  9. Biological age measured by DNA methylation clocks and frailty: a systematic review and meta-analysis.
  10. Clonal Hematopoiesis Risk Score (CHRS) Evaluation as a Prognostic Marker for Death in Cardio-Oncology Cohort.
  1. Mol Syst Biol. 2025 Nov 13.
    Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets.
    Anuar Makhmut, Mihnea P Dragomir, Sonja Fritzsche, Markus Moebs, Wolfgang D Schmitt, Eliane T Taube, Fabian Coscia.
      High-grade serous ovarian cancer (HGSOC) is often detected at an advanced stage, where curative treatment options are limited. Recent advances in ultrasensitive mass spectrometry-based spatial proteomics have provided a unique opportunity to uncover molecular drivers of early tumorigenesis and novel therapeutic targets. Here, we present a comprehensive proteomic analysis of serous tubal intraepithelial carcinoma (STIC), the HGSOC precursor lesion, and concurrent invasive carcinoma, covering more than 10,000 proteins from ultra-low input archival tissue. STIC and HGSOC showed highly similar proteomes, clustering into two subtypes with distinct tumor-immune microenvironments and common remodeling of the extracellular matrix. We discovered cell-of-origin signatures from secretory fallopian tube epithelial cells in STICs and identified early dysregulated pathways of therapeutic relevance. Targeting cholesterol biosynthesis by inhibiting the terminal steps via DHCR7 showed therapeutic effects in ovarian cancer cell lines and synergized with standard-of-care carboplatin treatment. This study demonstrates the power of spatially resolved quantitative proteomics in understanding early carcinogenesis and provides a rich resource for biomarker and drug target research.
    Keywords:  Cancer Proteomics; High-Grade Serous Ovarian Cancer; Serous Tubal Intraepithelial Carcinoma; Spatial Tissue Proteomics
    DOI:  https://doi.org/10.1038/s44320-025-00168-4
  2. Cancer. 2025 Nov 15. 131(22): e70148
    Preferences of BRCA mutation carriers for attributes of risk-reducing surgical options for breast and ovarian cancer.
    Katherine C Fitch, Jui-Chen Yang, Emma S Ryan, Karen A Monuszko, Katherine N Penvose, Sue Friedman, Jennifer K Plichta, Haley A Moss, Shelby D Reed, Laura J Havrilesky.
       BACKGROUND: Risk-reducing surgeries are the most effective strategies for cancer prevention in patients with germline pathogenic variants in the BRCA1/BRCA2 genes; these surgeries are associated with early menopause, loss of childbearing potential, and cosmetic effects. The authors assessed women's preferences for tradeoffs related to risk-reducing surgical decision making.
    METHODS: Carriers of pathogenic mutations in BRCA1/BRCA2 aged 25-50 years without a personal history of breast, ovarian, peritoneal, or tubal cancer were recruited to complete one of four discrete choice surveys based on their age (younger than 40 years or 40 years and older) and BRCA mutation status (BRCA1 or BRCA2). Participants responded to a series of choices between a do-nothing strategy and two profiles representing various effects of surgical options on menopause, childbearing potential (those younger than 40 years only), breast appearance, and 10-year and lifetime risks of breast and ovarian cancer. A conditional logit model was used to quantify participants' choices as a function of surgical options and outcomes.
    RESULTS: In total, 298 participants completed the survey. Each cohort younger than <40 years more frequently chose profiles representing risk-reducing salpingo-oophorectomy (RRSO) at age 40 versus 30 years. The cohort aged 40 years and older with BRCA1 mutations favored RRSO at age 40 years but with a 56.6% choice probability of delayed RRSO after ages 35-40 years, as recommended by National Comprehensive Cancer Network guidelines. The cohort aged 40 and older with BRCA2 mutations favored RRSO at age 40, 45, or 50 years fairly equally, with a 33.0% choice probability of guideline-nonconcordant RRSO timing. All cohorts favored mastectomy at younger ages and with reconstruction versus no mastectomy.
    CONCLUSIONS: These findings demonstrate the heterogeneity of preferences and support individualized discussion of treatment goals relating to risk-reducing surgical planning.
    Keywords:  BRCA; discrete‐choice experiment; hereditary breast cancer; hereditary ovarian cancer; risk reduction
    DOI:  https://doi.org/10.1002/cncr.70148
  3. Nat Genet. 2025 Nov;57(11): 2620
    Somatic mutations at scale.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02438-1
  4. Cancer. 2025 Nov 15. 131(22): e70160
    At the brink of a paradigm shift in early cancer detection: Insights and directions for the modeling community.
    Özge Karanfil, Zeynep Akşin, Raheelah Ahmad, Rifat Atun, Maarten Ijzerman, Dian Kusuma, Sandra Sülz, Nina Zhu.
      Multicancer early detection (MCED) tests are more than a new class of blood-based tests; they are complex medical innovations representing an integrated diagnostic platform combining molecular and computational technologies. They embody a paradigm shift in how to conceptualize, detect, and manage cancer-carrying the potential to improve outcomes and reduce disparities, yet also the risk of exacerbating them. Real-world evidence remains limited, and existing evidence point to substantial heterogeneity even in standard-of-care screening practices-reflecting patterns of overuse and underuse, fluctuations, and practice variation-despite notable advances in cancer treatment and technology over time. Integrating complex medical innovations into equally complex health systems poses significant challenges, underscoring the urgent need for model-based policy guidance to support their incorporation as a complement to population-based screening within standard-of-care pathways. In this editorial, existing policy-oriented dynamic simulation models on MCED tests are summarized, and insights on how modeling frameworks should evolve in parallel with the growing complexity of medical technologies are offered. Traditional approaches often rest on the implicit assumption that evidence reviews lead linearly to interpretation, policy, and adoption-without accounting for feedback between these stages. Evidence-based guideline formation as a feedback process is revisited as is how modelers develop a suite of flexible models tailored to distinct policy questions. Models that coexist and evolve iteratively as new evidence emerges, thereby capturing the adaptive and evolving nature of the problem itself. Such an approach must transcend disciplinary silos, enabling the integration of diverse data sources and supporting innovative portfolio approaches with methodological flexibility.
    Keywords:  MCED; biomarkers; complex systems; diffusion of innovation; early detection of cancer; evidence‐based medicine; genomics; liquid biopsy; practice guidelines; simulations
    DOI:  https://doi.org/10.1002/cncr.70160
  5. Int J Mol Sci. 2025 Nov 06. pii: 10792. [Epub ahead of print]26(21):
    Cell-Free DNA Hypermethylation in Patients with Acute Pancreatitis.
    Hassan Al-Mashat, Daniel Roger Baddoo, Søren Lundbye-Christensen, Poul Henning Madsen, Inge Søkilde Pedersen, Henrik B Krarup, Benjamin Emil Stubbe, Ole Thorlacius-Ussing, Stine Dam Henriksen.
      Cell-free DNA (cfDNA) promoter hypermethylation shows promise as a blood-based biomarker for pancreatic cancer, and similar alterations may occur in acute pancreatitis (AP). This study investigated the cfDNA hypermethylation profile of AP patients over time, compared with healthy controls, and its association with AP severity markers. A prospective longitudinal study including hospitalized AP patients and healthy controls was conducted. Methylation-specific PCR of a 23-gene panel was performed on plasma collected at inclusion (T0), 6 weeks (T6W), 6 months (T6M), and 7-8 years (T8Y). Associations between gene hypermethylation and clinical markers of AP severity-CRP, leukocyte count, creatinine, hospital stay, and complications-were evaluated. AP patients had a significantly higher mean number of hypermethylated genes at T0 (7.4, 95% CI: 6.8-8.0) compared with the controls (3.3, 95% CI: 2.8-3.8; p < 0.01). The mean number decreased over time to 3.2 (95% CI: 2.4-4.1) at T8Y. Total hypermethylation was positively associated with CRP (ρ = 0.39; p = 0.0018), leukocytes (ρ = 0.35; p = 0.0052), and hospital stay (ρ = 0.27; p = 0.0375). AP patients exhibited significantly higher cfDNA hypermethylation at disease onset, which normalized over time. Total hypermethylation showed positive associations with several markers of AP severity.
    Keywords:  acute pancreatitis; cell-free DNA; epigenetic; hypermethylation; methylation
    DOI:  https://doi.org/10.3390/ijms262110792
  6. Eur J Cancer. 2025 Nov 05. pii: S0959-8049(25)00983-9. [Epub ahead of print]231 116097
    Characterization of the cell-free DNA released by tumor organoids derived from colorectal cancer patients.
    Alexia Mirandola, Jérôme Cartry, Sabrina Bedja, Ekaterina Pisareva, Corinne Prevostel, Céline Gongora, Benjamin Ginter, Antoine Italiano, Michel Ducreux, Alice Boilève, Jacques R R Mathieu, Fanny Jaulin, Alain R Thierry.
       INTRODUCTION: Patient-derived tumor organoids (PDTOs) have histological, molecular and clinical (drug sensitivity) characteristics comparable to those of their originating tumors. However, little is known about their ability to replicate the release of tumor-derived DNA.
    METHODS: Supernatants from 21 colorectal cancer PDTO cultures, established from 13 patients, were prospectively collected. The presence, structure, and mutational landscape of nuclear (cf-nDNA) and mitochondrial (cf-mtDNA) cell-free DNA as well as extracellular mitochondria (ex-Mito) were analyzed using qPCR, fragmentomics and shallow whole-genome sequencing. Mutation profiling was performed via IntPlex qPCR and whole-exome sequencing (WES).
    RESULTS: Cf-nDNA was detected in 95 % of PDTO supernatants with concentrations ranging from 0.009 to 209 ng/mL. Cf-nDNA fragment size analysis revealed patterns consistent with circulating DNA, including mononucleosome-associated profile. Cf-mtDNA was present in all samples (0.27-89.2 pg/mL) and extracellular mitochondria was also detected (0.009-17.4 pg/mL). A strong concordance (>85 %) was observed between oncogenic mutations in cfDNA and the molecular alterations detected in PDTOs and patient tumors.
    CONCLUSION: PDTOs release both nuclear and mitochondrial cfDNA into their culture medium displaying high similarity with patient-derived circulating DNA (cirDNA), including fragmentation patterns and oncogenic mutations. This study strengthens the relevance of the PDTOs as patient tumors models and highlights the potential of analyzing PDTO-derived cfDNA as a non-invasive approach to investigate tumor evolution and as a valuable tool to support functional precision oncology.
    Keywords:  Cell-free DNA (cfDNA); Circulating DNA; Fragmentomics; Patient-derived tumor organoids (PDTOs)
    DOI:  https://doi.org/10.1016/j.ejca.2025.116097
  7. Bio Protoc. 2025 Nov 05. 15(21): e5488
    Library Preparation for Genome-Wide DNA Methylation Profiling.
    Fei-Man Hsu, Matteo Pellegrini, Pao-Yang Chen.
      DNA methylation is a fundamental epigenetic mark with critical roles in epigenetic regulation, development, and genome stability across diverse organisms. Whole genome bisulfite sequencing (WGBS) enables single-base resolution mapping of cytosine methylation patterns and has become a standard method in epigenomics. This protocol provides a detailed, step-by-step workflow for WGBS library construction starting from genomic DNA. It includes steps of RNaseA treatment, DNA shearing, end-repair and A-tailing, adapter ligation, bisulfite conversion, library amplification, and quantification. Notably, the method uses self-prepared reagents and customizable index systems, avoiding the constraints of commercial library preparation kits. This flexibility supports cost-effective, scalable methylome profiling, suitable for diverse experimental designs, including high-throughput multiplexed sequencing. Key features • Provides a comprehensive workflow for whole-genome bisulfite sequencing (WGBS) library preparation without relying on commercial kits. • Enables flexible multiplexing by allowing users to customize index systems during oligonucleotide synthesis. • Offers high-resolution, unbiased DNA methylation profiling at single-base resolution. • Optimized for cost-effective and scalable applications, including high-throughput sample processing. • Compatible with a wide range of DNA inputs and adaptable to different species and experimental designs.
    Keywords:  DNA methylation; Epigenetics; Epigenomics; Library preparation; Next generation sequencing; Whole genome bisulfite sequencing
    DOI:  https://doi.org/10.21769/BioProtoc.5488
  8. Commun Biol. 2025 Nov 12. 8(1): 1554
    Open chromatin-guided interpretable machine learning reveals cancer-specific chromatin features in cell-free DNA.
    Sakuntha D Gunarathna, Aerica Nagornyuk, Nazim A Belabbaci, Regina Nguyen, Bappa Ghosh, Sabha Ganai, Tabatha Lemke, Cassy Garry, Mika Saotome, Muhan Yu, Mamoru Takada, Xusheng Wang, Motoki Takaku.
      Cell-free DNAs (cfDNAs) are DNA fragments found in blood, originating mainly from immune cells in healthy individuals and from both immune and cancer cells in cancer patients. While cancer-derived cfDNAs carry mutations, they also retain epigenetic features such as DNA methylation and nucleosome positioning. In this study, we examine nucleosome enrichment patterns in cfDNAs from breast and pancreatic cancer patients and find significant enrichment at open chromatin regions. Differential enrichment is observed not only at cancer cell type specific ATAC-seq peaks but also at CD4+ T cell specific peaks, suggesting both tumor- and immune-derived contributions to the cfDNA signal. To leverage these patterns, we apply an interpretable machine learning model (XGBoost) trained on cell type specific open chromatin regions. This approach improves cancer detection accuracy and highlights key genomic loci associated with the disease state. Our pipeline provides a robust and interpretable framework for cfDNA-based cancer detection.
    DOI:  https://doi.org/10.1038/s42003-025-08920-0
  9. Lancet Healthy Longev. 2026 Oct 07. pii: S2666-7568(25)00092-3. [Epub ahead of print] 100773
    Biological age measured by DNA methylation clocks and frailty: a systematic review and meta-analysis.
    Jian Hua Tay, Duarte Barros, Weilan Wang, Vanessa Kristina Wazny, Andrea B Maier.
       BACKGROUND: Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.
    METHODS: In a systematic search of six databases (Embase, Cochrane Central Register of Controlled Trials, PubMed, Ovid, Scopus, and Web of Science) from Jan 1, 2011, to June 6, 2025, we identified population-based cohort studies reporting associations between DNA methylation age, EAA, or age deviation and frailty from general or disease-specific populations with a control group. Risk of bias was assessed using an adapted Newcastle-Ottawa Scale. Random-effects meta-analyses with Hartung-Knapp adjustments were performed on standardised β coefficients and SEs. Publication bias, influence, and sensitivity analyses were conducted.
    FINDINGS: From 34 437 records screened, 24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28 325 participants (14 757 [52·1%] female; median of mean age 65·2 years [IQR 62·2-69·4]). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11 162; standardised β coefficient 0·06 [95% CI 0·02-0·09], I2=71·4%), PhenoAge EAA (eight studies; n=10 371; 0·07 [0·03-0·11], I2=81·7%), GrimAge EAA (eight studies; n=10 371; 0·11 [0·06-0·15], I2=90·5%), and pace of ageing (five studies; n=7895; 0·10 [0·01-0·19], I2=91·0%) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6143; 0·02 [0·00-0·05], I2=46·0%, p=0·0481) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.
    INTERPRETATION: Higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.
    FUNDING: National University of Singapore.
    DOI:  https://doi.org/10.1016/j.lanhl.2025.100773
  10. JACC Adv. 2025 Nov 07. pii: S2772-963X(25)00719-7. [Epub ahead of print]4(12 Pt 2): 102290
    Clonal Hematopoiesis Risk Score (CHRS) Evaluation as a Prognostic Marker for Death in Cardio-Oncology Cohort.
    Jaiveer Singh, Rachel Jaber Chehayeb, Yunju Im, Irvin Yi, Talal El Zarif, Ana Ferrigno Guajardo, Jennifer VanOudenhove, Stephanie Halene, Alok Jha, Jennifer M Kwan.
      
    Keywords:  Clonal Hematopoiesis Risk Score (CHRS); cardio-oncology; clonal hematopoiesis of indeterminate potential (CHIP); mortality; outcomes; prognosis; risk
    DOI:  https://doi.org/10.1016/j.jacadv.2025.102290
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