bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–07–06
eleven papers selected by
Lara Paracchini, Humanitas Research
  1. Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer.
  2. Pan-cancer copy number analysis identifies optimized size thresholds and co-occurrence models for individualized risk stratification.
  3. Validation of adopting vaginal natural orifice transluminal endoscopic surgery for risk-reducing salpingo-oophorectomy for women with germline BRCA1/2 pathogenic variants analysis from conventional procedure.
  4. Identifying ovarian cancer with machine learning DNA methylation pattern analysis.
  5. The Somatic Mosaicism across Human Tissues Network.
  6. First human genome from ancient Egypt sequenced from 4,800-year-old teeth.
  7. HerediVar and HerediClassify: tools for streamlining genetic variant classification in hereditary breast and ovarian cancer.
  8. Rucaparib for maintenance treatment of platinum-sensitive, recurrent ovarian carcinoma: Final results of the phase 3, randomized, placebo-controlled ARIEL3 trial.
  9. Spatial profiling of chromatin accessibility in formalin-fixed paraffin-embedded tissues.
  10. Genomic landscape of virus-associated cancers.
  11. High-resolution detection of copy number alterations in single cells with HiScanner.
  1. Nat Commun. 2025 Jul 01. 16(1): 5586
    Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer.
    Scottish Genomes Partnership
      Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. Here, we comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N = 324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we find high mtDNA mutation loads associated with shorter patient survival. We show that a combination of mutations in the mitochondrial and nuclear genomes impact prognosis, suggesting strategies for patient stratification.
    DOI:  https://doi.org/10.1038/s41467-025-60655-y
  2. Nat Commun. 2025 Jul 02. 16(1): 6024
    Pan-cancer copy number analysis identifies optimized size thresholds and co-occurrence models for individualized risk stratification.
    Minh P Nguyen, William C Chen, Kanish Mirchia, Abrar Choudhury, Naomi Zakimi, Vijay Nitturi, Tiemo J Klisch, Stephen T Magill, Calixto-Hope G Lucas, Akash J Patel, David R Raleigh.
      Chromosome instability leading to aneuploidy and accumulation of copy number gains or losses is a hallmark of cancer. Copy number alteration (CNA) signatures are increasingly used for cancer risk stratification, but size thresholds for defining CNAs across cancers are variable and the biological and clinical implications of CNA size heterogeneity and co-occurrence are incompletely understood. Here we analyze CNA and clinical data from 691 meningiomas and 10,383 tumors from The Cancer Genome Atlas to develop cancer- and chromosome-specific size-dependent CNA and CNA co-occurrence models to predict tumor control and overall survival. Our results shed light on technical considerations for biomarker development and reveal prognostic CNAs with optimized size thresholds and co-occurrence patterns that refine risk stratification across a diversity of cancer types. These data suggest that consideration of CNA size, focality, number, and co-occurrence can be used to identify biomarkers of aggressive tumor behavior that may be useful for individualized risk stratification.
    DOI:  https://doi.org/10.1038/s41467-025-61063-y
  3. Obstet Gynecol Sci. 2025 Jul 03.
    Validation of adopting vaginal natural orifice transluminal endoscopic surgery for risk-reducing salpingo-oophorectomy for women with germline BRCA1/2 pathogenic variants analysis from conventional procedure.
    Hidetaka Nomura, Akiko Abe, Atsushi Fusegi, Mayumi Kamata, Arisa Ueki, Hiroyuki Kanao.
       Objective: Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is less invasive than conventional transabdominal laparoscopic surgery for benign gynecological indications. When adopting this procedure for risk-reducing salpingo-oophorectomy (RRSO) in women with hereditary breast and ovarian cancer (HBOC), the ventral side of the uterus becomes a blind area, which is a challenge. To clarify the effects of this blind area on the treatment outcome of HBOC, we examined the clinical data of RRSO using conventional procedures for women with germline BRCA1/2 pathogenic variants who were treated at our institution.
    Methods: A retrospective chart review was performed. The clinical data of patients who underwent RRSO using the conventional procedure between 2011 and July 2024 were extracted. All included patients were preoperatively examined using vaginal ultrasonography, contrast-enhanced pelvic magnetic resonance imaging, and carcinoma antigen-125 level measurements to exclude ovarian cancer development.
    Results: A total of 267 patients underwent RRSO at our institution. The mean age at RRSO was 50.1 years. Five cases of occult invasive cancer (1.9%) and 10 cases of serous tubal intraepithelial carcinoma (3.7%) were identified postoperatively. One patient (0.37%) showed macroscopic peritoneal dissemination in the omentum. None of the 252 patients without occult cancer developed peritoneal cancer during the mean observational time of 62.4 months No patient presented with peritoneal lesions ventral to the uterus.
    Conclusion: Macroscopic tumors on the peritoneum ventral to the uterus were rare when strict preoperative screening for ovarian cancer was performed. vNOTES can be safely adopted for RRSO in patients with HBOC, without evident disadvantages.
    Keywords:  Hereditary breast and ovarian cancer; Laparoscopic surgery; Ovarian cancer; Risk-reducing surgery; vNOTES
    DOI:  https://doi.org/10.5468/ogs.25044
  4. Sci Rep. 2025 Jul 01. 15(1): 20910
    Identifying ovarian cancer with machine learning DNA methylation pattern analysis.
    Jesus Gonzalez Bosquet, Vincent M Wagner, Douglas Russo, Henry D Reyes, Andreea M Newtson, David P Bender, Michael J Goodheart.
      The majority of patients with epithelial ovarian cancer (EOC) continue to be diagnosed at an advanced stage despite great advances in this disease treatment. To impact overall survival, we need better methods of EOC early diagnosis. We performed a case control study to predict high-grade serous cancer (HGSC) using artificial intelligence methodology and methylated DNA from surgical specimens. Initial prediction models with MethylNet were accurate but complex (AUC = 100%). We optimized these models by selecting the most informative probes with univariate ANOVA analyses first, and then multivariate lasso regression modelling. This step-wise approach resulted in 9 methylated probes predicting HGSC with an AUC of 100%. These models were validated with different analytics and with an independent DNA-methylation experiment with excellent performances.
    DOI:  https://doi.org/10.1038/s41598-025-05460-9
  5. Nature. 2025 Jul;643(8070): 47-59
    The Somatic Mosaicism across Human Tissues Network.
    Somatic Mosaicism across Human Tissues Network
      From fertilization onwards, the cells of the human body acquire variations in their DNA sequence, known as somatic mutations. These postzygotic mutations arise from intrinsic errors in DNA replication and repair, as well as from exposure to mutagens. Somatic mutations have been implicated in some diseases, but a fundamental understanding of the frequency, type and patterns of mutations across healthy human tissues has been limited. This is primarily due to the small proportion of cells harbouring specific somatic variants within an individual, making them more challenging to detect than inherited variants. Here we describe the Somatic Mosaicism across Human Tissues Network, which aims to create a reference catalogue of somatic mutations and their clonal patterns across 19 different tissue sites from 150 non-diseased donors and develop new technologies and computational tools to detect somatic mutations and assess their phenotypic consequences, including clonal expansions. This strategy enables a comprehensive examination of the mutational landscape across the human body, and provides a comparison baseline for somatic mutation in diseases. This will lead to a deep understanding of somatic mutations and clonal expansions across the lifespan, as well as their roles in health, in ageing and, by comparison, in diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09096-7
  6. Nature. 2025 Jul 02.
    First human genome from ancient Egypt sequenced from 4,800-year-old teeth.
    Ewen Callaway.
      
    Keywords:  Evolution; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-02102-y
  7. Hum Genomics. 2025 Jul 04. 19(1): 76
    HerediVar and HerediClassify: tools for streamlining genetic variant classification in hereditary breast and ovarian cancer.
    Anna-Lena Katzke, Marvin Doebel, Jan Hauke, Gunnar Schmidt, Marc Sturm.
       BACKGROUND: Multiple different evidence types as well as gene-specific variant classification guidelines need to be considered during the classification of variants, making the process complex. Therefore, tools that support variant classification by experts are urgently needed.
    METHODS: We present HerediVar a web application and HerediClassify a variant classification algorithm. The performance of HerediClassify was validated and compared to other variant classification tools. HerediClassify implements 19/28 variant classification criteria by the American College of Medical Genetics and gene-specific recommendations for ATM, BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53.
    RESULTS: HerediVar offers modular annotation services and allows for collaboration in the classification of variants. On the validation dataset, HerediClassify shows an average F1-Score of 93% across all criteria. HerediClassify outperforms other automated variant classification tools like vaRHC and Cancer SIGVAR.
    CONCLUSION: In HerediVar and HerediClassify we present a powerful solution to support variant classification in HBOC. Through their modular design, HerediVar and HerediClassify are easily extendable to other use cases and human genetic diagnostics as a whole.
    Keywords:  ACMG; Automated variant classification; Genetic diagnostics; Hereditary breast and ovarian cancer; Variant annotation; Variant classification
    DOI:  https://doi.org/10.1186/s40246-025-00787-w
  8. Eur J Cancer. 2025 Jun 17. pii: S0959-8049(25)00366-1. [Epub ahead of print]225 115584
    Rucaparib for maintenance treatment of platinum-sensitive, recurrent ovarian carcinoma: Final results of the phase 3, randomized, placebo-controlled ARIEL3 trial.
    Jonathan A Ledermann, Amit M Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I Weberpals, Andrew R Clamp, Giovanni Scambia, Alexandra Leary, Robert W Holloway, Margarita Amenedo Gancedo, Peter C Fong, Jeffrey C Goh, David M O'Malley, Deborah K Armstrong, Susana Banerjee, Jesús García-Donas, Elizabeth M Swisher, Coriolan Lebreton, Gottfried E Konecny, Iain A McNeish, Clare L Scott, Lara Maloney, Sandra Goble, Kevin K Lin, Robert L Coleman.
       BACKGROUND: In ARIEL3, rucaparib maintenance significantly improved progression-free survival (PFS; primary endpoint) and long-term follow-up (LTFU) outcomes (including PFS2: time to disease progression on subsequent therapy or death) versus placebo in patients with recurrent, platinum-sensitive ovarian cancer. Here we report the final analysis of overall survival (OS; key secondary endpoint), LTFU outcomes, and safety.
    METHODS: OS and updated LTFU efficacy outcomes were analyzed (data cutoff date: April 4, 2022) across three nested populations (BRCA-mutated, homologous recombination deficient [HRD], and intention to treat [ITT]).
    RESULTS: Patients were randomized 2:1 to rucaparib (600 mg BID; n = 375) or placebo (n = 189). Median follow-up was 77.0 months. 168 patients in the placebo arm received subsequent treatment; of these, 77 (46 %) received a poly(ADP-ribose) polymerase inhibitor-containing treatment. Median OS from randomization post chemotherapy for rucaparib vs placebo was 45.9 vs 47.8 months (HR 0.83, 95 % CI 0.58-1.19) for the BRCA-mutated population; no OS benefit was found with rucaparib in the HRD and ITT populations. Median PFS2 for rucaparib vs placebo was 26.1 vs 18.4 months (HR 0.67, 95 % CI 0.48-0.94) for the BRCA-mutated population. Rucaparib numerically improved PFS2 and other LTFU outcomes versus placebo in the HRD and ITT populations. Safety was consistent with prior reports; myelodysplastic syndrome and/or acute myeloid leukemia occurred in 4 % and 3 % of patients in the rucaparib and placebo arms, respectively.
    CONCLUSIONS: OS was similar between treatment arms. PFS benefit with rucaparib was maintained through the subsequent therapy line. These data support rucaparib as maintenance treatment for recurrent ovarian carcinoma.
    Keywords:  BRCA; Homologous recombination deficient; Long-term follow-up; Overall survival; PFS2; Poly(ADP-ribose) polymerase inhibitor; Progression-free interval; Recurrent ovarian cancer
    DOI:  https://doi.org/10.1016/j.ejca.2025.115584
  9. Nat Commun. 2025 Jul 01. 16(1): 5945
    Spatial profiling of chromatin accessibility in formalin-fixed paraffin-embedded tissues.
    Pengfei Guo, Yufan Chen, Liran Mao, Angelysia Cardilla, Chin Nien Lee, Yan Cui, Dengge Jin, Yucong Hua, Xiaowei Xu, Yanxiang Deng.
      Formalin-fixed paraffin-embedded (FFPE) samples represent a vast, untapped resource for epigenomic research, yet molecular tools for deep analysis of these specimens remain limited. We introduce spatial FFPE-ATAC-seq, an approach for in situ profiling chromatin accessibility within archived tissues. This approach overcomes formalin-induced crosslinking challenges, allowing high-resolution mapping of chromatin landscapes while preserving tissue architecture. Applying spatial FFPE-ATAC-seq to mouse and human tissues, including brain and thymus, reveals intricate spatial organization and distinct cell types in alignment with tissue morphology. Integration with single-cell RNA sequencing validates the precision of our chromatin profiles in identifying key cell types and regulatory elements. We further apply this method to human melanoma, comprehensively characterizing chromatin accessibility across both tumor and non-tumor regions. This method significantly expands the toolkit for epigenomic research, unlocking the potential of an extensive collection of archived FFPE samples for studying gene regulation and disease mechanisms with spatial context.
    DOI:  https://doi.org/10.1038/s41467-025-60882-3
  10. Nat Commun. 2025 Jul 01. 16(1): 5887
    Genomic landscape of virus-associated cancers.
    Yoonhee Nam, Karen Gomez, Jean-Baptiste Reynier, Cole Khamnei, Michael Aitken, Vivian Zheng, Tenzin Lhakhang, Milena Casula, Giuseppe Palmieri, Antonio Cossu, Arnold Levine, Enrico Tiacci, Raul Rabadan.
      It has been estimated that 15%-20% of human cancers are attributable to infections, mostly by carcinogenic viruses. The incidence varies worldwide, with a majority affecting developing countries. Here, we conduct a comparative analysis of virus-positive and virus-negative tumors in nine cancers linked to five viruses. We observe a higher frequency of virus-positive tumors in males, with notable geographic differences in incidence. Our genomic analysis of 1971 tumors reveals a lower somatic burden, distinct mutation signatures, and driver gene mutations in virus-positive tumors. Compared to virus-negative cases, virus-positive cases have fewer mutations of TP53, CDKN2A, and deletions of 9p21.3/CDKN2A-CDKN1A while exhibiting more mutations in RNA helicases DDX3X and EIF4A1. Furthermore, an analysis of clinical trials of PD-(L)1 inhibitors suggests an association of virus-positivity with higher treatment response rate, particularly evident in gastric cancer and head and neck squamous cell carcinoma. Both cancer types also show evidence of increased CD8 + T cell infiltration and T cell receptor clonal selection in virus-positive tumors. These results illustrate the epidemiological, genetic, and therapeutic trends across virus-associated malignancies.
    DOI:  https://doi.org/10.1038/s41467-025-60836-9
  11. Nat Commun. 2025 Jul 01. 16(1): 5477
    High-resolution detection of copy number alterations in single cells with HiScanner.
    Yifan Zhao, Lovelace J Luquette, Alexander D Veit, Xiaochen Wang, Ruibin Xi, Vinayak V Viswanadham, Yuwei Zhang, Diane D Shao, Christopher A Walsh, Hong Wei Yang, Mark D Johnson, Peter J Park.
      Improvements in single-cell whole-genome sequencing (scWGS) assays have enabled detailed characterization of somatic copy number alterations (CNAs) at the single-cell level. Yet, current computational methods are mostly designed for detecting chromosome-scale changes in cancer samples with low sequencing coverage. Here, we introduce HiScanner (High-resolution Single-Cell Allelic copy Number callER), which combines read depth, B-allele frequency, and haplotype phasing to identify CNAs with high resolution. In simulated data, HiScanner consistently outperforms state-of-the-art methods across various CNA types and sizes. When applied to high-coverage scWGS data from 65 cells across 11 neurotypical human brains, HiScanner shows a superior ability to detect smaller CNAs, uncovering distinct CNA patterns between neurons and oligodendrocytes. We also generated low-coverage scWGS data from 179 cells sampled from the same meningioma patient at two time points. For this serial dataset, integration of CNAs with point mutations revealed evolutionary trajectories of tumor cells. These findings show that HiScanner enables accurate characterization of frequency, clonality, and distribution of CNAs at the single-cell level in both non-neoplastic and neoplastic cells.
    DOI:  https://doi.org/10.1038/s41467-025-60446-5
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