bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–07–13
fourteen papers selected by
Lara Paracchini, Humanitas Research



  1. Acta Cytol. 2025 Jul 08. 1-31
       INTRODUCTION: Fallopian tube cytology is an evolving and as yet not well-established field. Through this study, we aimed to establish the utility of fallopian tube brush cytology by stratification into cytological diagnostic categories.
    METHODS: Cytological specimens were collected using an endobrush from the fimbrial end of the tubes at the time of gynaecological surgeries, and LBC preparation (Liquid-based cy-tology slides prepared by SurePath technique) and cell blocks were prepared. Smears were stratified into: Unsatisfactory/Non-diagnostic (ND), Benign, Atypical, Suspicious of Malig-nancy (SOM), and Malignant. Correlation with histopathology was done, and the Risk of Malignancy (ROM) was calculated for each category. Negative Predictive Value (NPV) and positive Predictive Value (PPV) were calculated. Diagnostic accuracy was calculated.
    RESULTS: A total of 392 tubal cytology specimens of 225 patients were collected. 8.2% (n=32) of the specimens were Unsatisfactory/Non-Diagnostic (ND), 87% (n=343) were Benign, 2.6% (n=10) were Atypical, 0.8% (n=3) were SOM, and 1% (n=4) were Malignant. All the cases in the SOM and malignant categories were serous carcinomas on histopathology. Of the ten atypical cases, all were non-malignant on histopathology: two were Serous Tubal In-traepithelial Lesions (STILs) and negative for Serous Tubal Intraepithelial Carcinoma (STIC), four showed salpingitis, and four showed normal histology. ROM for non-diagnostic, benign, and atypical categories was 0%. ROM for the malignant category, as well as the SOM category, was 100%. NPV for the benign category, benign and atypical categories, was 100%. PPV for the malignant category, as well as the malignant and SOM catego-ries, was 100%. Cellblocks were prepared for all cases, and the grey zone categories of atypical and SOM were reduced from 13 to 8. The diagnostic accuracy was 91.3% without and 99.4% with consideration of the Non-Diagnostic category.
    CONCLUSION: Fallopian tube brush cytology shows excellent concordance with the follow-up histopathology in all categories, barring the ND category. Excellent concordance with histo-pathology was seen in cases of the benign category, which comprised the majority of the samples (87.5%). Although excellent concordance was also seen in the other categories with the final histopathology, the number of samples in these categories was less for a definite conclusion. Cell block preparation, though useful, especially in the grey zone categories, did not offer statistically significant results. Another important finding was that not even a single case of incidental STIC was found. This finding raises questions on the accepted current rou-tine practice of preventive salpingectomy for all in the correct setting.
    DOI:  https://doi.org/10.1159/000546944
  2. Int J Gynecol Pathol. 2025 Jun 25.
      Junctions between different types of epithelia are hotspots for carcinogenesis. The peritoneal mesothelium of the mesovarium transitions to the ovarian surface epithelium at the ovarian hilus (the ovarian surface epithelium-peritoneal junction). There are limited histologic data on this junction in humans. We examined 143 examples of this junctional region in 76 patients with normal ovaries and in 150 patients with extrauterine high-grade serous carcinoma (HGSC). In the absence of significant pathologic processes in the region, this is normally a clearly demarcated, quiescent junction that is usually present directly over the interface of the ovarian stroma with the fibrovascular tissue of the mesovarium. When the ovarian surface epithelium (OSE) and mesothelial linings are well-preserved, the epithelial change at this junction is clearly visible when the OSE is cuboidal or columnar (seen in 79%). When the OSE is flat, no junction is visible (21%). The junction is sharply demarcated in 69%, and in 10% the OSE displays a progressively shorter epithelial height in its transition to the flat mesothelium. Transitional cell metaplasia occurs in the immediate vicinity in 11% of cases. In women with HGSC, tumor was present within 2 mm of this region in 41%. Carcinoma was confined to the ovarian/peritoneal surface in 15% and invaded the stroma without surface involvement in 16%. Carcinoma involved both the surface and invaded the underlying stroma in 11%. In our previous report from this cohort, 40% had serous tubal intraepithelial carcinoma (STIC). In the junctional region, intraepithelial HGSC was seen at the ovarian or peritoneal surface or within ovarian surface epithelial inclusions in 7 cases. Among these 7, fallopian tube tissue was evaluable in 5, and STIC was present in 2 (40%). Our findings characterize the histologic features of the normal ovarian surface epithelium-peritoneal junction and the involvement of this region in extrauterine HGSC.
    Keywords:  Epithelial junction; Fallopian tube carcinoma; High grade serous carcinoma; Mesothelium; Mesovarium; Ovarian carcinoma; Ovary; Peritoneum; Surface epithelium; Transition zone; Transitional cell metaplasia; Walthard cell nest
    DOI:  https://doi.org/10.1097/PGP.0000000000001121
  3. EBioMedicine. 2025 Jul 08. pii: S2352-3964(25)00274-9. [Epub ahead of print]118 105830
    Estonian Biobank Research Team
       BACKGROUND: Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined.
    METHODS: Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan.
    FINDINGS: GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells.
    INTERPRETATION: Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer.
    FUNDING: This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.
    Keywords:  Endometrial carcinoma; GWAS; Luciferase; NAV3; eQTL
    DOI:  https://doi.org/10.1016/j.ebiom.2025.105830
  4. bioRxiv. 2025 Jun 30. pii: 2025.06.29.660377. [Epub ahead of print]
      The epigenetic deregulation of CpG islands (CGIs) plays a crucial role in cancer initiation and progression. CGIs comprise 1-2% of the human genome and are rich in differentially methylated regions (DMRs) that can serve as cancer biomarkers in clinical samples and liquid biopsies. Focusing epigenetic sequencing on CpG-rich sequences, including CGIs and avoiding non-informative regions, offers an efficient and sensitive approach for cancer identification and tracking, especially within samples containing excess of unaltered, normal DNA. To this end, we have developed Adaptor-anchored Methylation amplification via Proximity Primers (aMAPP), a versatile PCR-based enrichment method. aMAPP employs specially designed primers to selectively enrich either methylated or unmethylated CpGs, depending on the upstream methylation conversion method employed. aMAPP achieves high coverage of genome-wide CGIs and detects hundreds of DMRs in tumor samples compared to adjacent normal tissue using ultra-low depth sequencing (∼300,000 reads). It enables tracing of aberrant methylation down to allelic frequency 0.01% in dilutions of tumor DNA and in cell-free DNA samples, can be applied using picogram amounts of DNA, and can be adapted to enrich either small panels of cancer-specific DMRs, or the majority (>90%) of genomic CGIs and CpGs. aMAPP offers a simple, cost-effective, and highly sensitive approach for capturing the epigenetic footprint of genome-wide CpGs and identifying aberrantly methylated or un-methylated genomic regions.
    DOI:  https://doi.org/10.1101/2025.06.29.660377
  5. N Engl J Med. 2025 Jul 10. pii: 10.1056/NEJMc2507106#sa1. [Epub ahead of print]393(2): 203-204
      
    DOI:  https://doi.org/10.1056/NEJMc2507106
  6. N Engl J Med. 2025 Jul 10. pii: 10.1056/NEJMc2507106#sa2. [Epub ahead of print]393(2): 204-205
      
    DOI:  https://doi.org/10.1056/NEJMc2507106
  7. Nature. 2025 Jul 08.
      
    Keywords:  Cancer; Genetics; Medical research; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-025-02053-4
  8. Cancer Prev Res (Phila). 2025 Jul 07.
      Identifying the presence of tumors at a very early stage or deciphering the process underlying their development can enable the interception of pro-malignant mechanisms underpinning cancer emergence, facilitating more effective prevention. Advances in molecular profiling allow the detection of genetic, epigenetic, immune, and microenvironmental alterations associated with cancer risk. Liquid biopsy permits non-invasive analysis of circulating tumor cells, nucleic acids, immune cells, extracellular vesicles, proteins, cytokines, and metabolites, while metagenome analysis facilitates gut microbiota profiling. Multi-cancer early detection (MCED) assays broaden this approach, capturing signals from multiple malignancies using a single blood sample. These technologies go beyond genomics, addressing immune dysregulation and metabolic shifts and may help identify gut microbiota imbalances. Clonal hematopoiesis of indeterminate potential (CHIP) gets increasing recognition of biomarker. Cardiovascular risk scores based on multiple parameters are an inspiring example The analysis of a combination of cancer drivers and enablers should provide a more sensitive and personalized measure of cancer prodromic profiles. Artificial intelligence will further support this transition by integrating molecular, immune, and metabolic data to develop individualized risk profiles. This shift from single-cancer detection to integrated, mechanism-based screening fosters a more proactive prevention model.. This combination early detection empowers cancer interception by using strategies including lifestyle modification, nutritional optimization, drug repurposing, pharmacologic interventions, and targeted chemoprevention. Moving beyond single parameters analysis and organ-specific screening, this multidimensional approach advances early detection and interception as practical clinical goals, facilitating the fundamental aim of positioning prevention at the forefront of oncology.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-24-0558
  9. Genes Dev. 2025 Jul 10.
      Ovarian aging is a critical yet understudied driver of systemic aging in female bodies, with profound implications for female health and longevity. Despite its significance, we still know little about ovarian aging and its systemic effects on aging trajectories. With new efforts over the past few years, interest in the field has been growing and there is momentum to address these questions. This review highlights the importance of leveraging modern tools and approaches to better understand ovarian aging and its impact on health span. Specifically, we believe it will be useful for both aging researchers looking to go into research on ovarian aging and reproductive researchers looking to adopt more modern toolkit. We focus on menopause-a key marker of ovarian aging-as a lens through which to examine the current state of the field, identify limitations in existing research, and outline goals for future progress. By emphasizing cutting-edge techniques and emerging models, we seek to illuminate new pathways for research that could lead to improved strategies for managing ovarian aging and enhancing overall female health.
    Keywords:  biomarkers; menopause; ovarian aging
    DOI:  https://doi.org/10.1101/gad.352732.125
  10. J Natl Cancer Inst. 2025 Jul 07. pii: djaf177. [Epub ahead of print]
       BACKGROUND: We investigated safety of breastfeeding after breast cancer in patients carrying germline BRCA pathogenic or likely pathogenic variants.
    METHODS: This was an international, multicentre, hospital-based, retrospective cohort study including BRCA carriers diagnosed with stage I-III invasive breast cancer at age 40 years or younger between January 2000 and December 2020 (NCT03673306). Locoregional recurrences and/or contralateral breast cancers, disease-free survival (DFS) and overall survival (OS) were compared between patients who breastfed after delivery and those who did not.
    RESULTS: Among 4732 patients included from 78 centres worldwide, 659 had a pregnancy after breast cancer diagnosis, of whom 474 delivered a child. After excluding patients with uptake of bilateral risk-reducing mastectomy prior to delivery (n = 225) or unknown breastfeeding status (n = 71), 110 (61.8%) breastfed (median duration 5 months) and 68 (38.2%) did not breastfeed. Compared to patients in the no breastfeeding group, those who breastfed were more frequently nulliparous at breast cancer diagnosis (61.8% vs 45.6%) and did not report prior smoking habit (71.8% vs 57.4%).After a median follow up of 7.0 years following delivery, 7-year cumulative incidence of locoregional recurrences and/or contralateral breast cancers was 29% in the breastfeeding group and 37% in the no breastfeeding group (adjusted subdistribution hazard ratio[HR]=1.08, 95%CI 0.57-2.06). No difference in DFS (aHR = 0.83, 95%CI 0.49-1.41) nor in OS (aHR = 1.32, 95%CI 0.31-5.66) was observed.
    CONCLUSIONS: Breastfeeding did not appear to be associated with a higher risk of developing locoregional recurrences or contralateral breast cancers, emphasizing the possibility of achieving a balance between maternal and infant needs without compromising oncological safety.
    DOI:  https://doi.org/10.1093/jnci/djaf177
  11. Clin Cancer Res. 2025 Jul 08.
       PURPOSE: No universal circulating biomarker exists for soft tissue (STS) and bone sarcoma (BS). We report the translational relevance of a droplet digital PCR (ddPCR) assay allowing universal, specific and dynamic detection of sarcoma-related hypermethylated circulating tumor DNA (ctDNA).
    EXPERIMENTAL DESIGN: In-silico analysis (TCGA/GEO datasets, n=8330) identified hypermethylated DNA positions in STS/BS, unmethylated in non-sarcoma tissues or white blood cells releasing circulating plasma cell-free DNA (cfDNA). A ddPCR assay following bisulfite conversion of cfDNA was developed. The methylation signature performances were evaluated in independent in-silico cohorts (TCGA/GEO, n=1342). The ddPCR assay was applied to cfDNA from healthy donors, patients with metastatic STS (METASARC cohort, n=49, 13 histotypes), and patients with STS/BS treated with neoadjuvant chemotherapy (NEOSARC cohort, n=42, 10 histotypes).
    RESULTS: A ddPCR assay targeting seven methylated genomic positions distinguished sarcoma samples versus non-neoplastic mesenchymal and endothelial/liver tissues (AUC=0.95; in silico validation set). Sensitivity allowed methylated DNA detection at 1:1000 dilution in genomic DNA, with a methylated allele frequency of 0.06%. CtDNA was positively detected in 45% of METASARC (22/49) and 74% of NEOSARC (31/42) patients, across all histotypes. CtDNA detection correlated with poor overall survival in METASARC patients with STS (p=0.039). Increasing ctDNA during neoadjuvant chemotherapy was associated with poor outcomes in NEOSARC (composite criteria with poor histological response, radiological progression or relapse within 6 months; p=0.0095).
    CONCLUSIONS: This sensitive ddPCR assay for universally methylated ctDNA enables precise detection, prognostication, and real-time monitoring of tumor burden in patients with high-grade and advanced sarcoma, regardless of histotype or origin.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-0134
  12. Nat Commun. 2025 Jul 09. 16(1): 6316
      Errors in chromosome segregation during gametogenesis, such as nondisjunction (NDJ) errors, have severe consequences in human reproduction, and a better understanding of their etiology is of fundamental interest in genetics. Mapping NDJ errors to meiotic/mitotic stages typically requires proband-parent comparison, limiting its applicability. Herein, we develop Mis-segregation Error Identification through Hidden Markov Models (MeiHMM), a method for inferring NDJ error stage and crossover events based on only genomic data of trisomic probands. Guided by triallelic genotype/haplotype configurations, MeiHMM discerns the allelic origin at each locus, which informs NDJ error during gamete formation, without identifying the parental origin of the trisomy. In 152 Down syndrome (DS) cases, MeiHMM achieved an accuracy of 96.1% in classifying NDJ errors, with a sensitivity of 91.6% in crossover identification, compared to proband-parents trio analysis. 17% of Meiosis II errors were misclassified as Meiosis I, mainly due to small proximal crossover events. Applying MeiHMM to 509 children with DS-associated childhood leukemia, we demonstrate that NDJ error is associated with the age of disease onset, somatic genomic abnormalities, and prognosis. Thus, MeiHMM is an effective method for trisomic NDJ error classification and crossover identification that can be applied broadly to study the etiology of congenital aneuploidy conditions.
    DOI:  https://doi.org/10.1038/s41467-025-61413-w