bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–05–18
eleven papers selected by
Lara Paracchini, Humanitas Research



  1. Lancet Oncol. 2025 May 07. pii: S1470-2045(25)00232-3. [Epub ahead of print]
      
    DOI:  https://doi.org/10.1016/S1470-2045(25)00232-3
  2. Nat Genet. 2025 May;57(5): 1189-1200
    Cancer Genome Atlas Analysis Network
      Genome conformation underlies transcriptional regulation by distal enhancers, and genomic rearrangements in cancer can alter critical regulatory interactions. Here we profiled the three-dimensional genome architecture and enhancer connectome of 69 tumor samples spanning 15 primary human cancer types from The Cancer Genome Atlas. We discovered the following three archetypes of enhancer usage for over 100 oncogenes across human cancers: static, selective gain or dynamic rewiring. Integrative analyses revealed the enhancer landscape of noncancer cells in the tumor microenvironment for genes related to immune escape. Deep whole-genome sequencing and enhancer connectome mapping provided accurate detection and validation of diverse structural variants across cancer genomes and revealed distinct enhancer rewiring consequences from noncoding point mutations, genomic inversions, translocations and focal amplifications. Extrachromosomal DNA promoted more extensive enhancer rewiring among several types of focal amplification mechanisms. These results suggest a systematic approach to understanding genome topology in cancer etiology and therapy.
    DOI:  https://doi.org/10.1038/s41588-025-02188-0
  3. Lancet Oncol. 2025 May 07. pii: S1470-2045(25)00152-4. [Epub ahead of print]
       BACKGROUND: Little evidence exists on the effect of risk-reducing surgeries in young BRCA carriers with a previous history of breast cancer. We investigated the association between risk-reducing mastectomy (RRM) or risk-reducing salpingo-oophorectomy (RRSO), or both procedures, with survival outcomes in a large global cohort of young BRCA carriers with previous breast cancer.
    METHODS: The BRCA BCY Collaboration is an international, hospital-based, retrospective cohort study, conducted at 109 centres in five continents, including women harbouring germline BRCA1, BRCA2, or both, pathogenic or likely pathogenic variants and diagnosed with stage I-III invasive breast cancer at the age of 40 years or younger between Jan 1, 2000, and Dec 31, 2020. The primary objectives of the present analysis were to determine the association between RRM or RRSO and overall survival in young BRCA carriers with breast cancer. The primary endpoint was overall survival. This study is registered with ClinicalTrials.gov, NCT03673306.
    FINDINGS: Between Jan 1, 2000 and Dec 31, 2020, 5290 patients were included, of whom 3361 (63·5%) patients were BRCA1 pathogenic variant carriers, 2708 (51·2%) had node-negative, and 2421 (45·8%) hormone receptor-positive breast cancer. Of 5290 patients, 2910 (55·0%) underwent RRM, 2782 (52·6%) underwent RRSO. After a median follow-up of 8·2 years (IQR 4·7-12·8), RRM was associated with significantly better overall survival compared with no RRM (adjusted HR [aHR] 0·65, 95% CI 0·53-0·78; 20-year restricted mean overall survival time 17·89 years [95% CI 17·61-18·17] with RRM vs 16·65 years [16·38-16·92] without RRM). RRSO was also associated with significantly better overall survival compared with no RRSO (aHR 0·58, 95% CI 0·48-0·71; 20-year restricted mean overall survival time 17·73 years [95% CI 17·43-18·03] with RRSO vs 16·67 years [16·38-16·96] without RRSO).
    INTERPRETATION: In this global cohort of BRCA carriers with previous breast cancer diagnosis at a young age, RRM and RRSO were both associated with a significant improvement in overall survival. These findings provide evidence for a tailored counselling of a unique and high-risk patient population on cancer risk management strategies.
    FUNDING: Italian Association for Cancer Research.
    DOI:  https://doi.org/10.1016/S1470-2045(25)00152-4
  4. Gynecol Oncol. 2025 May 09. pii: S0090-8258(25)00829-7. [Epub ahead of print]197 163-170
       BACKGROUND: Lynch syndrome causes increased risks of colorectal, endometrial, ovarian, and other cancers. Current guidelines for managing Lynch-associated ovarian and uterine cancer risks are vague and left to a clinician's discretion. This study aimed to identify factors associated with an individual's decision to undergo risk-reducing surgery or gynecologic screening.
    METHODS: A survey for individuals with Lynch syndrome was distributed to social media-based support groups. Eligible participants included individuals without a history of gynecologic cancer who had an intact uterus and/or ovaries when they were diagnosed with Lynch syndrome.
    RESULTS: The majority of the 115 participants identified as women (98.3 %), were age 30-49 (61.8 %), were non-Hispanic White (93.0 %), had a college degree or higher (80 %), were premenopausal at the time of genetic testing (69.6 %), had no prior cancer diagnosis (66.0 %), and had at least one biological child (73.9 %). Overall, 71 (61.8 %) participants completed risk-reducing surgery. The survey found that increasing age, having less than a college degree, having children, not desiring future pregnancies, menopausal status, and having a previous non-gynecologic cancer were significantly associated with choosing to undergo risk-reducing surgery. However, cancer risk factors, including family history of gynecologic cancer or which Lynch-associated gene was involved, were not associated with surgical decisions. Participant comments also provided insight into emotional factors experienced while navigating screening or surgical decisions.
    CONCLUSION: The results of this study may help clinicians better understand preventive decisions, which will ultimately empower patients to make confident, informed decisions about their gynecologic health.
    Keywords:  Decision-making; Gynecologic cancer; Lynch syndrome; Risk-reduction; Surveillance
    DOI:  https://doi.org/10.1016/j.ygyno.2025.05.003
  5. Clin Cancer Res. 2025 May 13.
       INTRODUCTION: Endometrial cancer is a common gynecologic malignancy lacks effective non-invasive screening tools, as traditional approaches rely on invasive biopsies. In this large prospective study, we evaluated a novel approach combining vaginal swab DNA and plasma-based circulating tumor DNA (ctDNA) for genomic profiling to provide a comprehensive framework for diagnosis, prognosis, and disease monitoring.
    MATERIALS AND METHODS: Adult patients with diverse stages of endometrial cancer, pre-neoplastic disease, and benign endometrial conditions were prospectively recruited over two years. Paired vaginal swab DNA and plasma-based ctDNA were collected pre-operatively, and additional plasma samples were obtained multiple time points post-operatively. Deep next-generation sequencing targeting 101 genes was performed, achieving an average depth exceeding 40,000x.
    RESULTS: A total of 191 patients contributed 388 samples. Vaginal swab DNA demonstrated 77.7% sensitivity and 96.6% specificity. PTEN mutations were associated with favorable prognosis (hazard ratio: 0.27; 95% CI: 0.092-0.77) and TP53 mutations were associated with poor prognosis (hazard ratio: 3.7; 95% CI: 1.4-10). A novel classification system based on the mutational profile of PTEN/TP53 identified distinct prognostic groups. Plasma-based ctDNA was significantly associated with stage, lymphovascular invasion, and prognosis (p < 0.01 for all). Patients with pre-operative positive plasma-based ctDNA results exhibited poorer outcomes (p < 0.01), whereas post-operative positive ctDNA enabled early detection of recurrence.
    DISCUSSION: These two non-invasive methods have distinct, complementary roles in the management of endometrial cancer. Vaginal swab DNA and novel PTEN/TP53-based classification have distinct prognostic advantages over existing frameworks. Plasma-based ctDNA provides dynamic insights into recurrence risk and disease progression.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-4263
  6. Lancet Oncol. 2025 May 07. pii: S1470-2045(25)00156-1. [Epub ahead of print]
       BACKGROUND: Carriers of BRCA1 and BRCA2 pathogenic variants are at elevated risk of developing breast and ovarian cancers. To mitigate ovarian cancer risk, bilateral salpingo-oophorectomy (BSO) is commonly recommended for unaffected carriers and those with personal breast cancer history. Assessing BSO's long-term health outcomes in carriers with previous breast cancer history is essential. This study aims to examine the association between BSO and long-term health outcomes in individuals carrying pathogenic variants in BRCA1 and BRCA2 and with personal history of breast cancer.
    METHODS: Data from the National Cancer Registration Dataset (NCRD) were linked with data from genetic testing laboratories to identify carriers of BRCA1 and BRCA2 pathogenic variants affected by breast cancer using pseudonymised patient identifiers. Further linkage to the Hospital Episode Statistics-Admitted Patient Care (HES-APC) dataset identified patients who had undergone BSO. Women aged 20-75 years, with a diagnosis of breast cancer as their first primary malignancy in 1995-2019 were eligible. Long-term health outcomes were identified from HES-APC and NCRD. Missing data were imputed using multivariate imputations by chained equations. Multivariable Cox regression was used to examine the associations with mortality (all-cause mortality, breast cancer-specific mortality, and non-breast cancer-specific mortality), second non-breast cancer, cardiovascular diseases, ischaemic heart disease, cerebrovascular diseases, contralateral breast cancer, and depression. Analyses were adjusted for age at diagnosis, diagnosis year, ethnicity, deprivation index, tumour characteristics, Charlson comorbidity index, cancer treatment, and second cancer diagnosis before the start of follow-up.
    FINDINGS: We included 1674 BRCA1, 1740 BRCA2, and nine BRCA1 and BRCA2 carriers who were diagnosed with breast cancer between 1995 and 2019, with median follow-up time of 5·5 years (IQR 3·4-8·2). The study population (n=3423) consisted of 3002 (88·7%) White, 170 (5·0%) Asian, 59 (1·7%) Black, 26 (0·8%) mixed, and 74 (2·2%) other ethnic groups, and 92 (2·7%) had missing ethnicity. The uptake of BSO was significantly lower among Black women (odds ratio [OR] vs White women 0·48, 95% CI 0·34-0·67), and Asian women (0·47, 0·27-0·82). BSO uptake was higher in women living in the least socioeconomically deprived areas (OR vs most deprived 1·38, 95% CI [1·10-1·72]). BSO was associated with a reduced risk of all-cause mortality for both BRCA1 and BRCA2 pathogenic variant carriers (HR 0·52, 95% CI 0·41-0·64) and reduced breast cancer-specific mortality (BRCA1: HR 0·62, 95% CI 0·42-0·92 and BRCA2: 0·48, 0·34-0·68). It was also associated with a reduced risk of second non-breast cancer in the combined BRCA1 and BRCA2 sample (HR 0·59, 95% CI 0·37-0·94). There BSO was not associated with increased risk of cardiovascular diseases (HR 0·73, 95% CI 0·53-1·01), ischaemic heart disease (1·04, 0·48-2·26), cerebrovascular disease (0·32, 0·11-0·90), non-breast cancer specific mortality (0·72, 0·45-1·16), contralateral breast cancer (1·18, 0·64-2·16), or depression (0·94, 0·62-1·42).
    INTERPRETATION: The evidence supports offering BSO to BRCA1 and BRCA2 pathogenic variant carrriers with a personal history of breast cancer, as they appear to benefit from having the procedure, without evidence of an increased risk of adverse long-term health outcomes.
    FUNDING: Cancer Research UK.
    DOI:  https://doi.org/10.1016/S1470-2045(25)00156-1
  7. J Exp Clin Cancer Res. 2025 May 15. 44(1): 144
       BACKGROUND: Hepatocellular carcinoma (HCC) is associated with a poor 5-year survival mainly due to detection at late stages. Better non-invasive surveillance methods are needed to improve early detection and maximize survival. We performed a strict assessment of DNA methylation markers (DMMs) for HCC detection.
    METHODS: A total of 385 samples from liver tissues and blood were analyzed. Genome-wide Methylated DNA sequencing (MeD-seq) was initially performed on 46 liver tissues, followed by the validation using quantitative methylation-specific PCR (qMSP) on 175 liver tissues. The selected DMMs with and without ASAP/GAAD score were further evaluated in 180 blood samples. Additionally, MeD-seq was performed to validate the results on blood.
    RESULTS: MeD-seq revealed a substantial number of differentially methylated regions (DMRs) in HCC tissues compared to non-HCC controls. By qMSP, the top 5 DMMs demonstrated strong performance in distinguishing cirrhotic HCC from cirrhosis controls in tissue (AUC 0.842 to 0.957). However, evaluation of these DMMs in blood showed lower performance in early HCC detection compared to cirrhosis in both the training (sensitivity 26.7-43.3%, 81.3% specificity) and validation cohorts (sensitivity 16.2-43.2%, 85.7% specificity). The addition of DMMs to the ASAP/GAAD score only provided an additional 5.4% sensitivity in the validation cohort compared to the ASAP/GAAD score alone. These findings were confirmed using MeD-seq analysis in blood samples, which revealed no detectable DMRs between cirrhotic HCC and cirrhosis controls. Interestingly, DNA methylation patterns in blood of healthy individuals differed strongly from both groups (cirrhosis and cirrhotic HCC).
    CONCLUSION: DNA methylation patterns in liver tissue were distinctly different between HCC and controls. In blood, DMMs contributed minimally to early-stage HCC detection compared to cirrhosis, whether used alone or in combination with the ASAP/GAAD score. It is likely that high baseline DNA methylation related to cirrhosis and possibly the low input of tumor-related DNA impacts the use of DMMs in early HCC detection in blood.
    Keywords:  Cell-free DNA; DNA methylation markers; Hepatocellular carcinoma; Methylated DNA sequencing
    DOI:  https://doi.org/10.1186/s13046-025-03412-9
  8. Eur J Surg Oncol. 2025 Apr;pii: S0748-7983(25)00073-3. [Epub ahead of print]51(4): 109645
      The absence of precise classification and effective predictive biomarkers in endometrial cancer (EC) leads to suboptimal treatment decisions and outcomes, underscoring the urgent need for improved diagnostic and therapeutic approaches. Endometrial cancer represents 4.8 % of the cases of malignant tumors, being in the sixth place worldwide in terms of incidence of malignant tumors in women. The treatment of endometrial cancer, especially stage I, which affects 70-75 % of patients, remains a subject of debate. According to the current European Society of Medical Oncology (ESMO) recommendations, for the management of patients with endometrial cancer, the treatment strategy is influenced by the results of risk stratification. Regarding endometrial cancer, a large number of prognostic factors are described, which create certain difficulties in their application in clinical practice. Most factors are morphological, and information about them is obtained after surgery on the basis of a standard histological examination. Of particular interest is the study of risk factors in the case of individual endometrial cancer variants. The molecular classification of endometrial tumors has the potential to become an indispensable element of histopathological classification, which would contribute to determining the prognosis and treatment strategies of the disease. In addition, it can lead to the development of a new targeted therapy, as well as to the implementation of molecular diagnostic tests for the detection of endometrial cancer in the early stages, when the prognosis is much more favorable. Despite the large amount of research which focuses on the study of the biological and molecular aspects of endometrial cancer, currently none of the tumor markers is recommended for widespread clinical use in endometrial cancer because there is insufficient information concerning their application into clinical practice.
    Keywords:  Biological aspects; Biomarker; Endometrial cancer; MSI (microsatellite instability); Molecular aspects; PTEN (tumor suppressor gene on chromosome 10); Precision medicine; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejso.2025.109645
  9. Nat Rev Genet. 2025 May 15.
      The causes and consequences of inequities in genomic research and medicine are complex and widespread. However, it is widely acknowledged that underrepresentation of diverse populations in human genetics research risks exacerbating existing health disparities. Efforts to improve diversity are ongoing, but an often-overlooked source of inequity is the choice of analytical methods used to process, analyse and interpret genomic data. This choice can influence all areas of genomic research, from genome-wide association studies and polygenic score development to variant prioritization and functional genomics. New statistical and machine learning techniques to understand, quantify and correct for the impact of biases in genomic data are emerging within the wider genomic research and genomic medicine ecosystems. At this crucial time point, it is important to clarify where improvements in methods and practices can, or cannot, have a role in improving equity in genomics. Here, we review existing approaches to promote equity and fairness in statistical analysis for genomics, and propose future methodological developments that are likely to yield the most impact for equity.
    DOI:  https://doi.org/10.1038/s41576-025-00839-w
  10. Nat Commun. 2025 May 13. 16(1): 4452
      Spatial transcriptomics has transformed our understanding of tissue architecture by preserving the spatial context of gene expression patterns. Simultaneously, advances in imaging AI have enabled extraction of morphological features describing the tissue. This review introduces a framework for categorizing methods that combine spatial transcriptomics with tissue morphology, focusing on either translating or integrating morphological features into spatial transcriptomics. Translation involves using morphology to predict gene expression, creating super-resolution maps or inferring genetic information from H&E-stained samples. Integration enriches spatial transcriptomics by identifying morphological features that complement gene expression. We also explore learning strategies and future directions for this emerging field.
    DOI:  https://doi.org/10.1038/s41467-025-58989-8