bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–09–28
eight papers selected by
Lara Paracchini, Humanitas Research
  1. Genomic landscapes of endometrioid and mucinous ovarian cancers and morphologically similar tumor types.
  2. Ovarian Cancer: Many Diseases Under One Name.
  3. Physician Peer Influence on Salpingectomy Uptake for Tubal Sterilization and Ovarian Cancer Prevention.
  4. Rapid epigenomic classification of acute leukemia.
  5. Reference genome choice compromises population genetic analyses.
  6. Uptake of Risk Reducing Mastectomy in Older BRCA1/2 and PALB2 Carriers Undergoing Genetic Testing after 60 Years of Age.
  7. Identification, functional insights and therapeutic targeting of EMT tumour states.
  8. Characterizing intra- and inter-tumor heterogeneity in Ovarian high-grade serous carcinoma subtypes using single-cell and spatial transcriptomics.
  1. Cancer Res Commun. 2025 Sep 22.
    Genomic landscapes of endometrioid and mucinous ovarian cancers and morphologically similar tumor types.
    Dorothy Hallberg, Alice C Eastman, Shashikant Koul, Daniel C Bruhm, Eniko Papp, Simon Davenport, Vilmos Adleff, Leonardo Ferreira, Noushin Niknafs, Jamie E Medina, Stephen Cristiano, Carolyn Hruban, Jacob Fiksel, Kaui P Lebarbenchon, Luis Aparicio, Nicholas A Vulpescu, Kuan-Ting Kuo, Nita Ahuja, Ronny Drapkin, Euihye Jung, Sarah H Kim, Mark A Eckert, Ernst Lengyel, Kentaro Nakayama, Ayse Ayhan, Ie-Ming Shih, Tian-Li Wang, Ofer Lavie, Gad Rennert, Hariharan Easwaran, Stephen B Baylin, Michael F Press, Victor E Velculescu, Robert B Scharpf.
      While endometrioid and mucinous ovarian carcinomas represent nearly a fifth of ovarian cancers, their molecular characteristics and pathologic origins are poorly understood. To identify the genomic and epigenomic alterations characteristic of these ovarian cancer subtypes and to evaluate links to morphologically similar tumors from other sites, we performed a combination of sequence, copy number, mutation signature, and rearrangement analyses from tumor samples and matched normal tissues of 133 patients, as well as methylation analyses of these tumors and tissues of 150 patients from The Cancer Genome Atlas. Genomic analyses included samples from patients with ovarian endometrioid (n=44), ovarian mucinous (n=43), uterine endometrioid (n=15), and gastrointestinal mucinous carcinomas (n=31), including mucinous carcinomas of the stomach, colon, and pancreas. In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4 and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous carcinomas. Whole genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid carcinomas, and NF1 and MED1 in ovarian mucinous carcinomas. The number of alterations, affected genes and genome-wide methylation profiles were not distinguishable between ovarian and uterine endometrioid carcinomas, supporting the hypothesis that these tumors share a tissue of origin. In contrast, mutation and methylation patterns in ovarian mucinous carcinomas were different from gastrointestinal mucinous carcinomas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0147
  2. J Insur Med. 2025 Sep 22.
    Ovarian Cancer: Many Diseases Under One Name.
    Clifton P Titcomb.
      In the United States, ovarian cancer is the second most common form of gynecologic cancer and the second leading cause of gynecologic cancer death. It is a heterogeneous disease with many different types and subtypes. The most common variety (70%-80%) is the high-grade serous epithelial tumor. A positive family history and/or the presence of susceptibility genes (BRCA1, BRCA2, and mismatch repair genes) increase the risk for developing the disease. Due to the lack of effective screening tools, even in those with known increased risk, most ovarian cancers are diagnosed at advanced stages. Diagnosis and accurate staging usually require tissue sampling and extensive debulking surgery performed by a surgeon who specializes in gynecologic oncology. Combination chemotherapy, before or after surgery, or as primary treatment for advanced disease is commonly needed. Mortality rates vary by stage, grade, and type of tumor. For the most common histotypes, due to the presence of advanced disease at presentation in most individuals, overall death rates remain high. Survival is better with some of the less common subtypes including sex cord stromal, germ cell and borderline epithelial ovarian tumors.
    Keywords:  BRCA1 and BRCA2; Epithelial ovarian tumors; borderline ovarian carcinoma; cancer antigen-125 (CA-125); carcinosarcoma; endometroid carcinoma; fallopian tube cancer; germ cell tumors; hereditary nonpolyposis coli/HNOCC/Lynch syndrome; high-grade serous carcinoma; human epididymis secretory protein-4 (HE-4); low-grade serous carcinoma; primary cancer of the peritoneum; primary mucinous carcinoma; sex cord - stromal tumors
    DOI:  https://doi.org/10.17849/insm-52-3-1-10.2A
  3. JAMA Netw Open. 2025 Sep 02. 8(9): e2532998
    Physician Peer Influence on Salpingectomy Uptake for Tubal Sterilization and Ovarian Cancer Prevention.
    Xiao Xu, Jessica B Long, Craig Evan Pollack, Vrunda B Desai, Cary P Gross, Erica S Spatz, Jason D Wright.
       Importance: Prophylactic removal of the fallopian tubes (opportunistic salpingectomy) in lieu of conventional methods of tubal sterilization helps reduce ovarian cancer risk.
    Objective: To examine how peer influence among physicians is associated with opportunistic salpingectomy uptake at the time of postpartum and interval sterilizations.
    Design, Setting, and Participants: This retrospective cohort study used insurance claims data from the Blue Cross Blue Shield Axis database. Participants were patients aged 18 to 49 years who underwent a tubal sterilization after childbirth (postpartum sterilization) or unrelated to pregnancy (interval sterilization) from January 2020 to December 2022 and whose operating surgeon did not perform opportunistic salpingectomy at baseline (2017-2019).
    Exposures: Applying a Louvain clustering methodology, physician patient-sharing networks were constructed based on their billing of the same patients in claims data at baseline (2017-2019). For surgeons who did not use opportunistic salpingectomy at baseline, the rate of opportunistic salpingectomy use among peer physicians in the same network at baseline was measured.
    Main Outcomes and Measures: Opportunistic salpingectomy was defined as removal of both (or the remaining side of) fallopian tubes with preservation of the ovaries.
    Results: The overall sample included 4520 patients undergoing postpartum sterilization and 3376 patients undergoing interval sterilization in 2020 to 2022, with 4173 (92.3%) of the postpartum sterilization sample involving a cesarean delivery. Most patients in these 2 samples (3520 patients [77.9%] and 2599 patients [77.0%], respectively) were aged 30 to 49 years. In the postpartum sterilization sample, having peer physicians in the highest (vs lowest) quartile of baseline opportunistic salpingectomy rate was associated with higher odds of receiving opportunistic salpingectomy for postpartum sterilization (13.6% vs 5.6%; adjusted odds ratio [aOR], 2.17; 95% CI, 1.20-3.92; P < .001). In the interval sterilization sample, having peer physicians in the highest (vs lowest) quartile of baseline opportunistic salpingectomy rate was also associated with higher odds of receiving opportunistic salpingectomy for interval sterilization (42.3% vs 19.3%; aOR, 4.16; 95% CI, 1.98-8.77; P < .001).
    Conclusions and Relevance: In this retrospective cohort study of postpartum and interval sterilizations, surgeons who previously shared patients with other physicians with high rates of opportunistic salpingectomy use were more likely to adopt opportunistic salpingectomy in their own subsequent practice. These results suggest physician peer influence in salpingectomy uptake.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.32998
  4. Nat Genet. 2025 Sep 22.
    Rapid epigenomic classification of acute leukemia.
    Til L Steinicke, Salvatore Benfatto, Maria R Capilla-Guerra, Andre B Monteleone, Jonathan H Young, Subha Shankar, Phillip D Michaels, Harrison K Tsai, Jonathan D Good, Antonia Kreso, Peter van Galen, Christoph Schliemann, Evan C Chen, Gabriel K Griffin, Volker Hovestadt.
      Acute leukemia requires precise molecular classification and urgent treatment. However, standard-of-care diagnostic tests are time-intensive and do not capture the full spectrum of acute leukemia heterogeneity. Here, we developed a framework to classify acute leukemia using genome-wide DNA methylation profiling. We first assembled a comprehensive reference cohort (n = 2,540 samples) and defined 38 methylation classes. Methylation-based classification matched standard-pathology lineage classification in most cases and revealed heterogeneity in addition to that captured by genetic categories. Using this reference, we developed a neural network (MARLIN; methylation- and AI-guided rapid leukemia subtype inference) for acute leukemia classification from sparse DNA methylation profiles. In retrospective cohorts profiled by nanopore sequencing, high-confidence predictions were concordant with conventional diagnoses in 25 out of 26 cases. Real-time MARLIN classification in patients with suspected acute leukemia provided accurate predictions in five out of five cases, which were typically generated within 2 h of sample receipt. In summary, we present a framework for rapid acute leukemia classification that complements and enhances standard-of-care diagnostics.
    DOI:  https://doi.org/10.1038/s41588-025-02321-z
  5. Cell. 2025 Sep 22. pii: S0092-8674(25)01026-8. [Epub ahead of print]
    Reference genome choice compromises population genetic analyses.
    Maria Akopyan, Matthew Genchev, Ellie E Armstrong, Jazlyn A Mooney.
      Characterizing genetic variation in natural populations is vital to evolutionary biology; however, many non-model species lack genomic resources. Here, we demonstrate that reference bias significantly affects population genomic analyses by mapping whole-genome sequence data from gray foxes (Urocyon cinereoargenteus) to a conspecific reference and two heterospecific canid genomes (dog and Arctic fox). Mapping to the conspecific genome improved read pairing by ∼5% and detected 26%-32% more SNPs and 33%-35% more singletons. Nucleotide diversity estimates increased by over 30%, FST increased from 0.189 to 0.197, and effective population size estimates were 30%-60% higher with the conspecific reference. Recombination rates varied by up to 3-fold at chromosome ends with heterospecific references. Importantly, FST outlier detection differed markedly, with heterospecific genomes identifying twice as many unique outlier windows. These findings highlight the impact of reference genome choice and the importance of conspecific genomic resources for accurate evolutionary inference.
    Keywords:  comparative genomics; conservation; demographic inference; population genetics; recombination; reference bias; selection scan
    DOI:  https://doi.org/10.1016/j.cell.2025.08.034
  6. Ann Surg Oncol. 2025 Sep 25.
    Uptake of Risk Reducing Mastectomy in Older BRCA1/2 and PALB2 Carriers Undergoing Genetic Testing after 60 Years of Age.
    Amel Melanson, Sarah Mashal, Carla Apostolova, Amina Ferroum, Mark Basik, Jean Francois Boileau, Karyne Martel, Sarkis Meterissian, Nora Wong, Evan Weber, William D Foulkes, Ipshita Prakash, Stephanie M Wong.
       BACKGROUND: The purpose of this study was to evaluate risk-reducing mastectomy (RRM) uptake in older BRCA1/2 and PALB2 carriers who undergo genetic testing after age 60 years.
    METHODS: We performed a multicentered retrospective cohort study of all female patients with a confirmed pathogenic variant in BRCA1/2 or PALB2 between 2003 and 2024. Women were categorized as having undergone genetic testing prior to or at/after 60 years of age, with clinical characteristics and risk management strategies compared between groups. Cox Proportional Hazards regression was then used to evaluate factors associated with RRM receipt.
    RESULTS: Of 814 BRCA1/2 and PALB2 carriers, 102 (12.5%) underwent genetic testing after age 60 years. At a median follow up of 56 months, 36 (35.3%) BRCA1/2 and PALB2 carriers tested over age 60 years underwent RRM. Uptake of RRM varied by personal history of breast cancer; in affected BRCA1/2 and PALB2 carriers, 47.6% of older patients underwent RRM compared with 78.9% of younger carriers (p < 0.001). In unaffected carriers, uptake of RRM was significantly lower among older patients (15.4% versus 40.3%, p = 0.008). In subgroup analysis of older carriers tested after age 60 years, factors associated with higher uptake of RRM included the presence of a BRCA1 or PALB2 variant (p < 0.005), personal history of breast cancer (p < 0.001), and no prior ovarian cancer (p = 0.005).
    CONCLUSIONS: Among BRCA1/2 and PALB2 carriers tested over the age of 60 years, 47.6% of affected carriers and 15.4% of unaffected carriers elected to undergo RRM. Further research evaluating optimal risk-management strategies in older carriers is warranted.
    Keywords:   BRCA1/2 ; Breast neoplasms; Chemotherapy; Hereditary breast cancer
    DOI:  https://doi.org/10.1245/s10434-025-18343-0
  7. Nat Rev Cancer. 2025 Sep 25.
    Identification, functional insights and therapeutic targeting of EMT tumour states.
    Anqi Dong, Cédric Blanpain.
      Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed.
    DOI:  https://doi.org/10.1038/s41568-025-00873-0
  8. bioRxiv. 2025 Sep 15. pii: 2025.09.15.676244. [Epub ahead of print]
    Characterizing intra- and inter-tumor heterogeneity in Ovarian high-grade serous carcinoma subtypes using single-cell and spatial transcriptomics.
    Weishan Li, Laurie Grieshober, Jason Gertz, Adriana Ivich, Jennifer A Doherty, Casey S Greene, Stephanie C Hicks.
      Ovarian high-grade serous carcinoma (HGSC) is an aggressive ovarian cancer with a heterogeneous tumor microenvironment (TME). Advances in single-cell RNA sequencing (scRNA-seq) and spatially-resolved transcriptomics have enabled the study of complex TME. This study explores connections between molecular subtypes described from bulk transcriptomes and spatial domains characterized by distinct gene expression in HGSC and their variability between patients. We explored both intraand inter-tumor heterogeneity across 2D space and identified differing spatial patterns of gene expression pertaining to immune pathways and vasculature development. Functional characterization of tumor spaces revealed potentially shared cell states across molecular subtypes, while correlation analysis underscored subtype-specific spatial anti-colocalization between spots exhibiting antigen-presenting functions and B cell-mediated immunity. Lastly, we performed spatially-aware cell-cell communication analysis on the spatial samples and identified a molecular subtype specific difference in total signaling activity and heterogeneity in Midikine signaling between the differentiated subtype. Our results suggest that generating multiple tissue slices per patient might be necessary to enable comprehensive characterization of HGSC spatial transcriptomes.
    DOI:  https://doi.org/10.1101/2025.09.15.676244
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