bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–10–05
nine papers selected by
Lara Paracchini, Humanitas Research
  1. Navigating dual risks: Ovarian cancer prevention and cardiovascular health in patients with hereditary cancer syndromes.
  2. Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA -deficient tubo-ovarian high-grade serous carcinoma.
  3. Publisher Correction: Multimodal cell maps as a foundation for structural and functional genomics.
  4. Tracking clonal evolution during treatment in ovarian cancer using cell-free DNA.
  5. Cell-free DNA fragmentomics in cancer.
  6. TP53 variant clusters stratify phenotypic diversity in germline carriers and reveal an osteosarcoma-prone subgroup.
  7. Dipping into the function of DNA methylation at centromeres.
  8. Comparison of somatic variant oncogenicity classification using ClinGen/CGC/VICC guidelines and QIAGEN Clinical Insight Interpret decision support software.
  9. The role of pyroptosis in ovarian cancer.
  1. Gynecol Oncol Rep. 2025 Oct;61 101940
    Navigating dual risks: Ovarian cancer prevention and cardiovascular health in patients with hereditary cancer syndromes.
    Laura Keenahan, Muhammad Danyal Ahsan, Alicia Mecklai, Melissa K Frey.
      •Surgical removal of ovaries and fallopian tubes is recommended for many hereditary cancer syndrome carriers before menopause.•Premature surgical menopause is associated with an increased risk of cardiovascular disease.•Clinicians caring for patients with premature surgical menopause should consider cardiovascular health implications.
    DOI:  https://doi.org/10.1016/j.gore.2025.101940
  2. medRxiv. 2025 Sep 22. pii: 2025.09.17.25335919. [Epub ahead of print]
    Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA -deficient tubo-ovarian high-grade serous carcinoma.
    Tibor A Zwimpfer, Sian Fereday, Ahwan Pandey, Dinuka Ariyaratne, Madawa W Jayawardana, Laura Twomey, Céline M Laumont, Catherine J Kennedy, Adelyn Bolithon, Nicola S Meagher, Katy Milne, Phineas Hamilton, Jennifer Alsop, Antonis C Antoniou, George Au-Yeung, Matthias W Beckmann, Amy Berrington de Gonzalez, Christiani Bisinotto, Freya Blome, Clara Bodelon, Jessica Boros, Alison H Brand, Michael E Carney, Alicia Cazorla-Jiménez, Derek S Chiu, Elizabeth L Christie, Anita Chudecka-Głaz, Penny Coulson, Kara L Cushing-Haugen, Cezary Cybulski, Kathleen M Darcy, Cath David, Trent Davidson, Arif B Ekici, Esther Elishaev, Julius Emons, Tobias Engler, Rhonda Farrell, Anna Fischer, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Prafull Ghatage, Rosalind Glasspool, Philipp Harter, Andreas D Hartkopf, Arndt Hartmann, Sebastian Heikaus, Brenda Y Hernandez, Anusha Hettiaratchi, Sabine Heublein, David G Huntsman, Mercedes Jimenez-Linan, Michael E Jones, Eunyoung Kang, Ewa Kaznowska, Tomasz Kluz, Felix K F Kommoss, Gottfried Konecny, Roy F P M Kruitwagen, Jessica Kwon, Diether Lambrechts, Cheng-Han Lee, Jenny Lester, Samuel C Y Leung, Yee Leung, Anna Linder, Jolanta Lissowska, Liselore Loverix, Jan Lubiński, Constantina Mateoiu, Iain A McNeish, Malak Moubarak, Gregg S Nelson, Nikilyn Nevins, Alexander B Olawaiye, Siel Olbrecht, Sandra Orsulic, Ana Osorio, Carmel M Quinn, Ganendra Raj Mohan, Isabelle Ray-Coquard, Cristina Rodríguez-Antona, Patricia Roxburgh, Matthias Ruebner, Stuart G Salfinger, Spinder Samra, Minouk J Schoemaker, Hans-Peter Sinn, Gabe S Sonke, Linda Steele, Colin J R Stewart, Aline Talhouk, Adeline Tan, Christopher M Tarney, Sarah E Taylor, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van-Wagensveld, Andrea E Wahner-Hendrickson, Christina Walter, Chen Wang, Julia Welz, Nicolas Wentzensen, Lynne R Wilkens, Stacey J Winham, Boris Winterhoff, Michael S Anglesio, Andrew Berchuck, Francisco J Candido Dos Reis, Paul A Cohen, Thomas P Conrads, Philip Crowe, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, María J García, Simon A Gayther, Marc T Goodman, Jacek Gronwald, Holly R Harris, Florian Heitz, Hugo M Horlings, Beth Y Karlan, Linda E Kelemen, G Larry Maxwell, Usha Menon, Francesmary Modugno, Susan L Neuhausen, Joellen M Schildkraut, Annette Staebler, Karin Sundfeldt, Anthony J Swerdlow, Ignace Vergote, Anna H Wu, James D Brenton, Paul D P Pharoah, Celeste Leigh Pearce, Malcolm C Pike, Ellen L Goode, Susan J Ramus, Martin Köbel, Brad H Nelson, Anna DeFazio, Michael L Friedlander, David D L Bowtell, Dale W Garsed.
      BRCA -associated homologous recombination deficiency (HRD) is present in ∼50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA -deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA -deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA -deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1 -deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2 -deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2 -deficient HGSC with exceptionally short survival. BRCA1 -deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (g BRCA pv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in g BRCA pv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA -deficient HGSC.
    DOI:  https://doi.org/10.1101/2025.09.17.25335919
  3. Nature. 2025 Oct 02.
    Publisher Correction: Multimodal cell maps as a foundation for structural and functional genomics.
    Leah V Schaffer, Mengzhou Hu, Gege Qian, Kyung-Mee Moon, Abantika Pal, Neelesh Soni, Andrew P Latham, Laura Pontano Vaites, Dorothy Tsai, Nicole M Mattson, Katherine Licon, Robin Bachelder, Anthony Cesnik, Ishan Gaur, Trang Le, William Leineweber, Aji Palar, Ernst Pulido, Yue Qin, Xiaoyu Zhao, Christopher Churas, Joanna Lenkiewicz, Jing Chen, Keiichiro Ono, Dexter Pratt, Peter Zage, Ignacia Echeverria, Andrej Sali, J Wade Harper, Steven P Gygi, Leonard J Foster, Edward L Huttlin, Emma Lundberg, Trey Ideker.
      
    DOI:  https://doi.org/10.1038/s41586-025-09648-x
  4. Nature. 2025 Oct 01.
    Tracking clonal evolution during treatment in ovarian cancer using cell-free DNA.
    Marc J Williams, Ignacio Vázquez-García, Grittney Tam, Michelle Wu, Nancy Varice, Eliyahu Havasov, Hongyu Shi, Duaa H Al-Rawi, Gryte Satas, Hannah J Lees, Jake June-Koo Lee, Matthew A Myers, Matthew Zatzman, Nicole Rusk, Emily Ali, Ronak H Shah, Michael F Berger, Neeman Mohibullah, Yulia Lakhman, Dennis S Chi, Nadeem R Abu-Rustum, Carol Aghajanian, Andrew McPherson, Dmitriy Zamarin, Brian Loomis, Britta Weigelt, Claire F Friedman, Sohrab P Shah.
      Emergence of drug resistance is the main cause of therapeutic failure in patients with high-grade serous ovarian cancer (HGSOC)1. To study drug resistance in patients, we developed CloneSeq-SV, which combines single-cell whole-genome sequencing2 with targeted deep sequencing of clone-specific genomic structural variants in time-series cell-free DNA. CloneSeq-SV exploits tumour clone-specific structural variants as highly sensitive endogenous cell-free DNA markers, enabling the relative abundance measurements and evolutionary analysis of co-existing clonal populations over the therapeutic time course. Here, using this approach, we studied 18 patients with HGSOC over a multi-year period from diagnosis to recurrence and showed that drug resistance typically arose from selective expansion of a single or small subset of clones present at diagnosis. Drug-resistant clones frequently showed interpretable and distinctive genomic features, including chromothripsis, whole-genome doubling, and high-level amplifications of oncogenes such as CCNE1, RAB25, MYC and NOTCH3. Phenotypic analysis of matched single-cell RNA sequencing data3 indicated pre-existing and clone-specific transcriptional states such as upregulation of epithelial-to-mesenchymal transition and VEGF pathways, linked to drug resistance. In one notable case, clone-specific ERBB2 amplification affected the efficacy of a secondary targeted therapy with a positive patient outcome. Together, our findings indicate that drug-resistant states in HGSOC pre-exist at diagnosis, leading to positive selection and reduced clonal complexity at relapse. We suggest these findings motivate investigation of evolution-informed adaptive treatment regimens to ablate drug resistance in future HGSOC studies.
    DOI:  https://doi.org/10.1038/s41586-025-09580-0
  5. Cancer Cell. 2025 Oct 02. pii: S1535-6108(25)00398-8. [Epub ahead of print]
    Cell-free DNA fragmentomics in cancer.
    W H Adrian Tsui, Peiyong Jiang, Y M Dennis Lo.
      The analysis of cell-free DNA (cfDNA) fragmentation patterns, known as "fragmentomics," has opened new opportunities in noninvasive cancer diagnostics. Due to its close relationships with genomic organization and cell death, cfDNA fragmentomics lies at the intersection of many aspects of cancer biology, including epigenetic dysregulation, transcriptomic alterations, and aberrant cellular turnover patterns. Recent advances in library preparation, sequencing technologies, and integrative epigenomic-fragmentomic analyses have uncovered novel fragmentomic features that reveal specific cellular dysfunctions in cancer. Additionally, cutting-edge artificial intelligence algorithms now harness high-dimensional fragmentomic features, boosting the precision and power of cancer detection. Promising results from recent clinical trials evaluating the utility of fragmentomic analyses in real-world settings support its potential. In this review, we explore the exciting frontiers of cfDNA fragmentomics, discuss critical unanswered questions, and highlight future directions to unlock the promise of fragmentomics-based liquid biopsies in cancer care.
    Keywords:  artificial intelligence; cancer detection; cancer risk prediction; cancer treatment monitoring; cell-free DNA; fragmentomics; machine learning
    DOI:  https://doi.org/10.1016/j.ccell.2025.09.006
  6. Nat Commun. 2025 Sep 29. 16(1): 8546
    TP53 variant clusters stratify phenotypic diversity in germline carriers and reveal an osteosarcoma-prone subgroup.
    Nicholas W Fischer, Noel Ong, Brianne Laverty, Pamela Psarianos, Camilla Giovino, Noa Alon, Emilie Montellier, Pierre Hainaut, Kara N Maxwell, Christian P Kratz, Ran Kafri, David Malkin.
      Li-Fraumeni syndrome (LFS) has recently been redefined as a 'spectrum' cancer predisposition disorder to reflect its broad phenotypic heterogeneity. This variability is thought to stem in part from the diverse functional impacts of TP53 variants, although the underlying mechanisms remain poorly understood and there is an unmet clinical need for effective risk stratification. Here, we apply unsupervised clustering to functional datasets and identify distinct TP53 variant groups with clinical relevance, including a monomeric subgroup enriched in osteosarcoma cases. In cellular validation assays, dermal fibroblasts from carriers of more functionally impaired variants exhibit increased metabolic growth rates, mirroring trends observed in cluster-stratified clinical outcomes. These findings demonstrate the feasibility of developing diagnostic assays to guide personalized cancer risk assessment. More broadly, our results show that nuances in TP53 dysfunction shape the germline TP53-related cancer susceptibility spectrum and provide a framework for functionally delineating variant carriers.
    DOI:  https://doi.org/10.1038/s41467-025-63528-6
  7. Nat Genet. 2025 Sep 29.
    Dipping into the function of DNA methylation at centromeres.
    Sylvia Erhardt.
      
    DOI:  https://doi.org/10.1038/s41588-025-02334-8
  8. Cancer Genet. 2025 Sep 18. pii: S2210-7762(25)00119-X. [Epub ahead of print]298-299 151-158
    Comparison of somatic variant oncogenicity classification using ClinGen/CGC/VICC guidelines and QIAGEN Clinical Insight Interpret decision support software.
    Aarthi Goverdhan, Lisa Mullineaux, Amber Pryzbylski, Claire Teigen, Kevin C Halling, Sheryl K Elkin, Beth A Pitel.
      Accurate clinical interpretation of somatic cancer variants is critical for diagnosis and guidance of precision oncology treatment. As the depth and breadth of genomic sequencing increased, laboratories developed independent standards for the classification of somatic variants. In response, a set of standards for classification were published by a collaboration among Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC) and Variant Interpretation for Cancer Consortium (VICC). This study evaluated these standards and compared the resulting classifications to the classifications generated by a clinical decision support software system, QIAGEN Clinical Insight (QCI) Interpret One, a system using a version of the 2015 consensus guidelines by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) customized for somatic assessment. The published variant set for validation was utilized and expanded by conducting a retrospective analysis using real-world cancer variants drawn from oncology cases tested at Mayo Clinic. For "oncogenic" and "likely oncogenic" variants in the combined datasets, automated classifications by the QCI system were 97.2% concordant with those assessed using the ClinGen/CGC/VICC system. The ClinGen/CGC/VICC standards led to more conservative variant classifications, with a larger proportion of variants assigned to the "variant of unknown significance" and "likely benign" designations. This study demonstrates that the ClinGen/CGC/VICC guidelines and clinical decision support tools can be effectively used together to facilitate somatic variant classification and interpretation.
    Keywords:  Classification; Oncogenicity; Oncology; Standards; Variant
    DOI:  https://doi.org/10.1016/j.cancergen.2025.09.009
  9. Discov Oncol. 2025 Oct 03. 16(1): 1806
    The role of pyroptosis in ovarian cancer.
    Yingzhi Zhou, Tian Peng, Jiahan Zhang, Ruojia Liang.
      Pyroptosis is a novel form of programmed cell death that depends on gasdermin-mediated pore formation in the plasma membrane and the release of inflammatory factors. Pyroptosis is closely linked to the occurrence and progression of almost all types of cancer, including ovarian cancer, which is the seventh most common malignancy among women worldwide and poses a significant threat to women's health. Research indicates that pyroptosis may offer potential strategies for monitoring and treating ovarian cancer. This review systematically discusses the molecular mechanisms of pyroptosis and its role in the onset, progression, prognosis, and treatment of ovarian cancer, providing deep insights for further research in this field.
    Keywords:  Gasdermin; Inflammasome; Ovarian cancer; Pyroptosis; Treatment
    DOI:  https://doi.org/10.1007/s12672-025-03518-8
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