bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–07–20
eleven papers selected by
Lara Paracchini, Humanitas Research
  1. Integrated Spatial Analysis of Ovarian Precancerous Lesions.
  2. Clinical utility of various liquid biopsy samples for the early detection of ovarian cancer: a comprehensive review.
  3. Genome doubling fuels ovarian cancer evolution and immune dysregulation.
  4. Tandem duplication and triplication in BRCA1: revisiting the large genomic rearrangements via optical genome mapping.
  5. Gastric cancer risk and BRCA1/2 mutations: a systematic review and meta-analysis.
  6. Direct genetic transformation bypasses tumor-associated DNA methylation alterations.
  7. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer.
  8. Transcriptome Analysis of Matched Cohorts of Long- and Short-term Survivors in Advanced High-Grade Serous Tubo-ovarian Cancer.
  9. Genetic Biomarkers Associated with Dynamic Transitions of Human Papillomavirus (HPV) Infection-Precancerous-Cancer of Cervix for Navigating Precision Prevention.
  10. Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy.
  11. Incidence of de novo migraine after premenopausal bilateral oophorectomy.
  1. bioRxiv. 2025 Jun 27. pii: 2025.06.24.661327. [Epub ahead of print]
    Integrated Spatial Analysis of Ovarian Precancerous Lesions.
    Tu-Yung Chang, Yen-Wei Chien, Szu-Hua Chen, Annelise Sokolow, Yeh Wang, Brant G Wang, Tricia Numan, M Herman Chui, Rebecca Stone, Thomas Pisanic, Nicholas 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 clinic-pathological features in 166 ovarian precancerous lesions. Four pre-cancerous subtypes were identified transcriptomically: 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, our 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/10.1101/2025.06.24.661327
  2. Front Oncol. 2025 ;15 1594100
    Clinical utility of various liquid biopsy samples for the early detection of ovarian cancer: a comprehensive review.
    Yueqi Feng, Wanjun Yang, Jingyu Zhu, Shirui Wang, Ningjuan Wu, Hanzhi Zhao, Xiaofeng Yang.
      Ovarian cancer (OC) is a highly lethal gynecologic malignancy because of the absence of specific early symptoms and reliable biomarkers, most OC patients are often diagnosed at advanced stages, resulting in poor prognosis. Traditional tissue biopsy and serological biomarkers like CA125 have limited clinical application. Therefore, there is an urgent demand for effective diagnostic and screening tools in clinical practice. Liquid biopsy is a non-invasive method for early cancer detection by analyzing tumor-associated components shed into different body fluids, for example, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cell-free RNA, proteins, and metabolites. Increasing evidence has demonstrated that liquid biopsy is promising for detecting cancer at an early stage. In this review, we outline the results for the utility of each liquid biopsy fluid, including serum/plasma, urine, cervical/vaginal sample, uterine lavage, and summarize the advantages and current constraints associated with their application in clinical settings. Future directions and challenges are also highlighted, along with areas where more research is warranted.
    Keywords:  biomarkers; early detection; liquid biopsy; multi-omics; ovarian cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1594100
  3. Nature. 2025 Jul 16.
    Genome doubling fuels ovarian cancer evolution and immune dysregulation.
    Nikki L Burdett, Elizabeth L Christie.
      
    Keywords:  Cancer; DNA sequencing; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-02059-y
  4. Cancer Genet. 2025 Jul 07. pii: S2210-7762(25)00081-X. [Epub ahead of print]296-297 125-129
    Tandem duplication and triplication in BRCA1: revisiting the large genomic rearrangements via optical genome mapping.
    B Aldrige Allister, Jonathan L Lühmann, Lena Wendeburg, Frank Dechend, Carmela Beger, Stefanie Tölle, Julia von Ehr, Tim Ripperger, Bernd Auber, Nataliya di Donato, Doris Steinemann.
      Large genomic rearrangements (LGRs) within the human genome are becoming more recognized by novel genome-wide technologies and may be underreported so far. This class of genomic variation includes copy number variations like duplications or triplications of coding or non-coding genomic regions. Here, we report two LGRs targeting BRCA1, a duplication of exons 18-19 and a triplication of exons 1-2 in two independent families. Utilizing Optical Genome Mapping (OGM), Whole Genome Sequencing (WGS) and cDNA analysis, we characterized the genomic organization and transcriptomic effects of these LGRs regarding its. We show that the tandem duplication ogm[GRCh38]dup(17)(q21.31q21.31)(43057052_43063373), targeting BRCA1 exon 18-19 is predicted to generate a premature termination codon, namely p.(His1732Metfs*10). The triplication of BRCA1 exon 1-2 ogm[GRCh38]trip(17)(q21.31q21.31)(43117155_43124115) is also sequentially arranged. The transcript shows an insertion of a small part of intron 2 (chr17:43,121,558-43,121,676) that theoretically will generate a premature termination codon as well. Collectively, OGM and WGS help elucidating the architecture of these LGRs. However, the final curation depends on how adequate the functional consequences of these LGR can be clarified. Deeper investigation of LGRs on transcript level is important to attain accurate conclusions with respect to therapeutic decisions.
    Keywords:  BRCA; HBOC; LGR; OGM; Tandem duplication; Tandem triplication; WGS
    DOI:  https://doi.org/10.1016/j.cancergen.2025.07.002
  5. Per Med. 2025 Jul 13. 1-12
    Gastric cancer risk and BRCA1/2 mutations: a systematic review and meta-analysis.
    Francisco Cezar Aquino de Moraes, Gustavo Tadeu Freitas Uchôa Matheus, Maria Eduarda Cavalcanti Souza, Rommel Mario Rodriguez Burbano.
       BACKGROUND: Gastric cancer is an aggressive and heterogeneous disease, primarily sporadic, with only 1-3% of cases being hereditary. However, gastric cancer is a component of several hereditary cancer syndromes. The BRCA1 and BRCA2 genes encode key DNA repair proteins involved in homologous recombination. Studies suggest a significantly increased risk of gastric cancer in first-degree relatives of BRCA1/2 mutation carriers.
    METHODS: We systematically searched PubMed, Scopus, and Web of Science for relevant studies. Risk ratios (RRs) with 95% confidence intervals (CIs) were computed using DerSimonian and Laird random-effect models. Heterogeneity was assessed via I2 statistics. Statistical analyses were performed using R (version 4.2.3).
    RESULTS: Fourteen studies with 160,551 patients were included, of whom 25,934 had BRCA1/2 mutations (BRCA1: 14322; BRCA2: 11612). BRCA1 and BRCA2 mutations were significantly associated with increased gastric cancer risk (RR 2.30; 95% CI: 1.33-3.97; p = 0.003; I2 = 82% and RR 2.45; 95% CI: 1.82-3.28; p < 0.001; I2 = 25%). Among the gastric cancer patients, BRCA1 and BRCA2 mutations were associated with RRs of 3.02 (p = 0.101; I2 = 65%) and 4.86 (p < 0.001; I2 = 0%), respectively.
    CONCLUSIONS: This meta-analysis suggests that BRCA1/2 mutation carriers have a higher risk of developing gastric cancer.
    Keywords:  BRCA1; BRCA2; cancer risk; cancer screening; gastric cancer; hereditary cancer; meta-analysis
    DOI:  https://doi.org/10.1080/17410541.2025.2531737
  6. Genome Biol. 2025 Jul 17. 26(1): 212
    Direct genetic transformation bypasses tumor-associated DNA methylation alterations.
    Sara Hetzel, Eran Hodis, Elena Torlai Triglia, Alexander Kovacsovics, Kathleen Steinmann, Andreas Gnirke, Meiying Cui, Daniel McQuaid, Raha Weigert, Georg Pohl, Mandar D Muzumdar, Serge Leyvraz, Ulrich Keilholz, Marie-Laure Yaspo, Aviv Regev, Helene Kretzmer, Zachary D Smith, Alexander Meissner.
       BACKGROUND: Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, there are key unresolved questions about the conditions that support a cell's initial transformation, which cannot be easily captured in patient populations and are instead modeled using transgenic cellular or animal systems.
    RESULTS: Here, we use extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and apply this benchmark to evaluate 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation rarely recapitulates the widespread de novo methylation of Polycomb regulated promoter sequences as found in clinical samples, but can trigger global changes in DNA methylation levels that are consistent with extensive proliferation in vitro.
    CONCLUSIONS: Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis as well as provide an important molecular reference for evaluating existing and emerging tumor models.
    Keywords:  Cancer; DNA methylation; Disease models; Epigenetics; Genetically engineered mouse models
    DOI:  https://doi.org/10.1186/s13059-025-03650-2
  7. Nature. 2025 Jul 16.
    Ongoing genome doubling shapes evolvability and immunity in ovarian cancer.
    Andrew McPherson, Ignacio Vázquez-García, Matthew A Myers, Duaa H Al-Rawi, Matthew Zatzman, Adam C Weiner, Samuel Freeman, Neeman Mohibullah, Gryte Satas, Marc J Williams, Nicholas Ceglia, Danguolė Norkūnaitė, Allen W Zhang, Jun Li, Jamie L P Lim, Michelle Wu, Seongmin Choi, Eliyahu Havasov, Diljot Grewal, Hongyu Shi, Minsoo Kim, Roland F Schwarz, Tom Kaufmann, Khanh Ngoc Dinh, Florian Uhlitz, Julie Tran, Yushi Wu, Ruchi Patel, Satish Ramakrishnan, DooA Kim, Justin Clarke, Hunter Green, Emily Ali, Melody DiBona, Nancy Varice, Ritika Kundra, Vance Broach, Ginger J Gardner, Kara Long Roche, Yukio Sonoda, Oliver Zivanovic, Sarah H Kim, Rachel N Grisham, Ying L Liu, Agnes Viale, Nicole Rusk, Yulia Lakhman, Lora H Ellenson, Simon Tavaré, Samuel Aparicio, Dennis S Chi, Carol Aghajanian, Nadeem R Abu-Rustum, Claire F Friedman, Dmitriy Zamarin, Britta Weigelt, Samuel F Bakhoum, Sohrab P Shah.
      Whole-genome doubling (WGD) is a common feature of human cancers and is linked to tumour progression, drug resistance, and metastasis1-6. Here we examine the impact of WGD on somatic evolution and immune evasion at single-cell resolution in patient tumours. Using single-cell whole-genome sequencing, we analysed 70 high-grade serous ovarian cancer samples from 41 patients (30,260 tumour genomes) and observed near-ubiquitous evidence that WGD is an ongoing mutational process. WGD was associated with increased cell-cell diversity and higher rates of chromosomal missegregation and consequent micronucleation. We developed a mutation-based WGD timing method called doubleTime to delineate specific modes by which WGD can drive tumour evolution, including early fixation followed by considerable diversification, multiple parallel WGD events on a pre-existing background of copy-number diversity, and evolutionarily late WGD in small clones and individual cells. Furthermore, using matched single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signalling and cGAS-STING pathway activation result from ongoing chromosomal instability, but this is restricted to predominantly diploid tumours (WGD-low). By contrast, predominantly WGD tumours (WGD-high), despite increased missegregation, exhibited cell-cycle dysregulation, STING1 repression, and immunosuppressive phenotypic states. Together, these findings establish WGD as an ongoing mutational process that promotes evolvability and dysregulated immunity in high-grade serous ovarian cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09240-3
  8. Clin Cancer Res. 2025 Jul 15.
    Transcriptome Analysis of Matched Cohorts of Long- and Short-term Survivors in Advanced High-Grade Serous Tubo-ovarian Cancer.
    Sofya Marchenko, Niklas Goernitz, Wiebke Alina Zoern, Maria Joosten, Inga Hoffmann, Jalid Sehouli, Gerald Niedobitek, Carsten Denkert, Bruno V Sinn, Svenja Kolb, José Carbonell-Caballero, Alfonso Valencia, Mihnea P Dragomir, Wolfgang D Schmitt, David Horst, Ioana I Braicu, Christine Sers, Jonathan Pohl, Eliane T Taube.
       OBJECTIVE: The late-stage diagnosis and the aggressiveness of high-grade serous tubo-ovarian carcinoma (HGSC) often results in poor survival outcomes, yet some patients exhibit an exceptionally long survival rate.This study aimed to identify molecular profiles associated with long-term/short-term survival in HGSC, with the goal of better understanding protective factors and developing new treatments.
    EXPERIMENTAL DESIGN: To discover molecular drivers causing aggressiveness of HGSC, tumor samples from 12 long-term HGSC survivors (> 7 years overall survival) and 12 short-term survivors (< 1 year overall survival) were analyzed using targeted RNA sequencing followed by computational analysis. We investigated differentially expressed genes and their functional relevance, inferred differences in cell-type composition and signaling pathways as well as mutation status. To validate our findings, we simulated our study design by using HGSC TCGA dataset samples. We evaluated differential patterns of gene expression between these two groups and developed molecular profiles of HGSC that correlate with survival phenotypes.
    RESULTS: Besides known molecular cancer drivers and indicators of poor prognosis, we identified specific transcriptional changes between short-term and long-term survivors of HGSC which indicate that immune processes play a fundamental role in long-term survivors. Our computational analysis reveals an important role of the ensemble of IFN-γ signaling and the RFX transcription factors as well as the immune cell composition of the tumor microenvironment.
    CONCLUSION: Specific immunologic requirements involving IFN-γ signaling and affected pathways seem to be relevant for long term survival in the generally considered non-immunogenic HGSC, requesting further research to improve diagnostic strategies and targeted therapies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2794
  9. Int J Mol Sci. 2025 Jun 23. pii: 6016. [Epub ahead of print]26(13):
    Genetic Biomarkers Associated with Dynamic Transitions of Human Papillomavirus (HPV) Infection-Precancerous-Cancer of Cervix for Navigating Precision Prevention.
    Pallop Siewchaisakul, Jean Ching-Yuan Fann, Meng-Kan Chen, Chen-Yang Hsu.
      Precision prevention strategies for cervical cancer that integrate genetic biomarkers provide opportunities for personalized risk assessment and optimized preventive measures. An HPV infection-Precancerous-Cancer risk assessment model incorporating genetic polymorphisms and DNA methylation was developed to better understand the regression and progression of cervical lesions by HPV infection status. Utilizing a virtual cohort of 300,000 Taiwanese women aged 30 years and older, our model simulated the natural history of cervical cancer, capturing transitions from a healthy state through precancerous lesions (LSILs and HSILs) to invasive carcinoma and incorporating the possibility of regression between states. Genetic and epigenetic markers significantly influenced disease transitions, demonstrating heterogeneous risks among women with distinct molecular biomarker profiles. Guided by these individual risk profiles, tailored preventive strategies including varying intervals for Pap smear screening, HPV DNA testing, and HPV vaccination showed improved efficiency and effectiveness in reducing cervical cancer incidence compared to uniform approaches. The proposed dynamic transition model of cervical neoplasms incorporating genetic biomarkers can facilitate the development of an individualized risk-based approach for guiding precision prevention towards the goal of cervical cancer elimination.
    Keywords:  HPV; cervical cancer; epigenetic factors; genetic factors; multistate disease evolution; nature history
    DOI:  https://doi.org/10.3390/ijms26136016
  10. Nat Genet. 2025 Jul 15.
    Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy.
    Jie Liu, Duc Tran, Liying Xue, Brian J Wiley, Caitlyn Vlasschaert, Caroline J Watson, Hamish A J MacGregor, Xiaoyu Zong, Irenaeus C C Chan, Indraniel Das, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Benjamin L Ebert, Taralynn Mack, Yash Pershad, Brian Sharber, Michael Berger, Ahmet Zehir, Ryan Ptashkin, Ross L Levine, Elli Papaemmanuil, Vijai Joseph, Teng Gao, Yelena Kemel, Diana Mandelker, Konrad H Stopsack, Paul D P Pharoah, Semanti Mukherjee, Li Ding, Yin Cao, Matthew J Walter, Jamie R Blundell, Nilanjan Chatterjee, Kenneth Offit, Lucy A Godley, Daniel C Link, Zsofia K Stadler, Alexander G Bick, Pradeep Natarajan, Kelly L Bolton.
      With age, clonal expansions occur pervasively across normal tissues yet only in rare instances lead to cancer, despite being driven by well-established cancer drivers. Characterization of the factors that influence clonal progression is needed to inform interventional approaches. Germline genetic variation influences cancer risk and shapes tumor mutational profile, but its influence on the mutational landscape of normal tissues is not well known. Here we studied the impact of germline genetic variation on clonal hematopoiesis (CH) in 731,835 individuals. We identified 22 new CH-predisposition genes, most of which predispose to CH driven by specific mutational events. CH-predisposition genes contribute to unique somatic landscapes, reflecting the influence of germline genetic backdrop on gene-specific CH fitness. Correspondingly, somatic-germline interactions influence the risk of CH progression to hematologic malignancies. These results demonstrate that germline genetic variation influences somatic evolution in the blood, findings that likely extend to other tissues.
    DOI:  https://doi.org/10.1038/s41588-025-02250-x
  11. Maturitas. 2025 Jul 03. pii: S0378-5122(25)00465-7. [Epub ahead of print]200 108657
    Incidence of de novo migraine after premenopausal bilateral oophorectomy.
    Samantha E Mannion, Carin Y Smith, Jennifer A Buzzard, Liliana Gazzuola Rocca, Jennifer St Sauver, Walter A Rocca, Ekta Kapoor.
       OBJECTIVE: Little is known about the effects of premenopausal bilateral oophorectomy on the development of migraine. We compared migraine outcomes for women undergoing oophorectomy with those of referent women.
    STUDY DESIGN: The cohort included 1243 women who underwent premenopausal bilateral oophorectomy in Olmsted County, MN, US between 1988 and 2007 and 1415 age-matched (±1 year) referent women. Women diagnosed with migraine before oophorectomy (or index) were excluded. Estrogen therapy after oophorectomy was assessed as a time-dependent factor.
    RESULTS: Women who underwent oophorectomy had an increased risk of de novo migraine compared with referent women (HR, 1.59; 95 % CI, 1.24-2.05). The risk was particularly higher for women who underwent oophorectomy under the age of 45 years. An increased risk of migraine without aura, but not of migraine with aura, was observed, as is characteristic of menstrual migraines. The risk of de novo migraine in the women with oophorectomy off estrogen was comparable to that of the referent women (HR, 0.80; 95 % CI, 0.43-1.52). By contrast, women with oophorectomy on estrogen had an increased risk of migraine (HR, 2.08; 95 % CI, 1.47-2.92).
    CONCLUSIONS: Premenopausal bilateral oophorectomy is associated with an increased risk of migraine. Although estrogen is known to mitigate the severity of menopause-related symptoms, the higher risk for migraine among women using estrogen could be the result of them being prescribed estrogen because of greater severity of menopause symptoms. We encourage future studies to examine how the type, dose, and route of estrogen impact migraine outcomes after oophorectomy.
    Keywords:  Bilateral oophorectomy; Early menopause; Estrogen; Iatrogenic menopause; Migraine headache; Premature menopause
    DOI:  https://doi.org/10.1016/j.maturitas.2025.108657
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