bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–04–06
ten papers selected by
Lara Paracchini, Humanitas Research
  1. The challenge of managing isolated STIC lesions: A single-center experience.
  2. CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.
  3. Copy number variations in endometrial cancer: from biological significance to clinical utility.
  4. Genome-wide cell-free DNA methylation profiling in advanced stage ovarian cancer. Are we looking at the tumor or the patient's immune response to the tumor?
  5. Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study.
  6. MUTYH: Possibly another important gene in ovarian cancer?
  7. Cell-cycle dependent DNA repair and replication unifies patterns of chromosome instability.
  8. Cell-free DNA Fragmentomics Assay to Discriminate the Malignancy of Breast Nodules and Evaluate Treatment Response.
  9. Multicancer early detection testing: Guidance for primary care discussions with patients.
  10. Cervical Cancer.
  1. Gynecol Oncol Rep. 2025 Apr;58 101716
    The challenge of managing isolated STIC lesions: A single-center experience.
    Renata Sabelli, Basile Tessier-Cloutier, Lili Fu, Shuk On Annie Leung, Xing Zeng, Reitan Ribeiro, Victoria Mandilaras, Lucy Gilbert, Laurence Bernard.
       Objectives: High-grade serous carcinoma (HGSC) arise from serous tubal intraepithelial carcinoma (STIC) lesions, a precursor that develops from the fallopian tube epithelium. Patients with incidental isolated STIC lesions found on salpingectomy specimen have up to 25% risk of developing HGSC or peritoneal carcinomatosis in the future, yet there is no established consensus to guide management.
    Methods: This retrospective case series includes patients diagnosed with isolated STIC lesions between April 2017 and January 2024. Patient data was extracted from clinical and pathological databases.
    Results: During the study period, 10 patients were diagnosed with an isolated STIC lesion. The fallopian tubes were removed either as part of a hysterectomy for endometrial cancer (n = 3); a prophylactic risk-reducing surgery for BRCA1 or BRCA2 mutation (n = 3); or a benign gynecologic condition (n = 4). The median age of the patients was 64 years (range: 53-80). Among patients who underwent genetic testing (n = 9), only three were found to have a deleterious germline mutation in BRCA1 or BRCA2. The patients either received adjuvant chemotherapy (n = 5) or underwent active surveillance (n = 5). One surveillance patient was managed with completion bilateral oophorectomy and omentectomy. Median number of chemotherapy cycles was four (range 4-6 cycles). The median follow-up was 27 months (range: 5-83 months). One patient under active surveillance was diagnosed with peritoneal carcinomatosis 5 years after initial diagnosis of STIC whereas none recurred in the chemotherapy group.
    Conclusion: The wide variety of treatment approaches we observed highlights a need for more data on this entity to support management guidelines.
    Keywords:  Adjuvant Chemotherapy; High-grade serous ovarian cancer (HGSC); Management & Treatment.; Peritoneal carcinomatosis (PC); Serous Tubal Intraepithelial Carcinoma (STIC)
    DOI:  https://doi.org/10.1016/j.gore.2025.101716
  2. PLoS Comput Biol. 2025 Apr 03. 21(4): e1012902
    CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.
    Khanh N Dinh, Ignacio Vázquez-García, Andrew Chan, Rhea Malhotra, Adam Weiner, Andrew W McPherson, Simon Tavaré.
      Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text] ). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012902
  3. Int J Gynecol Cancer. 2024 Jul;pii: S1048-891X(24)01441-5. [Epub ahead of print]34(7): 1089-1097
    Copy number variations in endometrial cancer: from biological significance to clinical utility.
    Erica Dugo, Francesco Piva, Matteo Giulietti, Luca Giannella, Andrea Ciavattini, Linda Gough.
      The molecular basis of endometrial cancer, which is the most common malignancy of the female reproductive organs, relies not only on onset of mutations but also on copy number variations, the latter consisting of gene gains or losses. In this review, we introduce copy number variations and discuss their involvement in endometrial cancer to determine the perspectives of clinical applicability. We performed a literature analysis on PubMed of publications over the past 30 years and annotated clinical information, including histological and molecular subtypes, adopted molecular techniques for identification of copy number variations, their locations, and the genes involved. We highlight correlations between the presence of some specific copy number variations and myometrial invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high grade, drug response, and cancer progression. In particular, type I endometrial cancer cells have few copy number variations and are mainly located in 8q and 1q, while type II, high grade, and advanced FIGO stage endometrial cancer cells are aneuploid and have a greater number of copy number variations. As expected, the higher the number of copy number variations the worse the prognosis, especially if they amplify CCNE1, ERBB2, KRAS, MYC, and PIK3CA oncogenes. Great variability in copy number and location among patients with the same endometrial cancer histological or molecular subtype emerged, making them interesting candidates to be explored for the improvement of patient stratification. Copy number variations have a role in endometrial cancer progression, and therefore their detection may be useful for more accurate prediction of prognosis. Unfortunately, only a few studies have been carried out on the role of copy number variations according to the molecular classification of endometrial cancer, and even fewer have explored the correlation with drugs. For these reasons, further studies, also using single cell RNA sequencing, are needed before reaching a clinical application.
    Keywords:  Carcinoma; Endometrial Neoplasms; Homologous recombination
    DOI:  https://doi.org/10.1136/ijgc-2024-005295
  4. Cancer Treat Res Commun. 2025 Mar 22. pii: S2468-2942(25)00041-3. [Epub ahead of print]43 100903
    Genome-wide cell-free DNA methylation profiling in advanced stage ovarian cancer. Are we looking at the tumor or the patient's immune response to the tumor?
    Caroline B van den Berg, Gatske M Nieuwenhuyzen-de Boer, Ingrid A Boere, Ruben G Boers, Joachim B Boers, Wilfred F J van-IJcken, Maurice P H M Jansen, Tugce S Kirmizitas, Joost H Gribnau, Heleen J van Beekhuizen.
      The aim of this study was to identify differentially methylated regions in cell-free DNA (cfDNA) between healthy persons and patients with advanced stage ovarian cancer (ASOC) and to identify differences in cfDNA methylation before and after cytoreductive surgery. Plasma-derived cfDNA was analyzed by a high-throughput genome wide DNA methylation sequencing technique: MeD-seq. A training set of therapy naïve cfDNA samples of patients with ASOC (≥FIGO stage IIIB, n=10) was compared with cfDNA of healthy controls (n=10) to define a ASOC specific cfDNA methylation signature. A cumulative hypermethylation score was constructed and a validation set of pre- and postoperative samples of 39 patients were compared using this score. MeD-seq results of tumor tissue samples were correlated with cfDNA results. Patients with ASOC showed a clear distinct cfDNA methylation signature from healthy controls (p<0.0001). This cfDNA-methylation signature resulted in preoperative hypermethylation scores (135; interquartile range 110-163) that were significantly higher than postoperative hypermethylation scores (91; interquartile range 76-101) (p<0.001). The cfDNA methylation signature at baseline differed from tumor tissue and was more closely related to DNA methylation of immune-related cells (T-lymphocytes, neutrophil granulocytes, monocytes, and B-lymphocytes) than to ASOC tissue. MeD-seq provides a promising method for genome wide methylation profiling of cfDNA. Patients with ASOC could clearly be distinguished from healthy controls and differed pre- and postoperatively.
    Keywords:  DNA methylation; Liquid biopsy; MeD-seq; Ovarian cancer; cell free DNA
    DOI:  https://doi.org/10.1016/j.ctarc.2025.100903
  5. ESMO Open. 2025 Apr 01. pii: S2059-7029(25)00402-8. [Epub ahead of print]10(4): 104533
    Benefit from maintenance with PARP inhibitor in newly diagnosed ovarian cancer according to BRCA1/2 mutation type and site: a multicenter real-world study.
    C Marchetti, A Fagotti, R Fruscio, C Cassani, L Incorvaia, M T Perri, C M Sassu, C A Camnasio, E Giudice, A Minucci, M Seca, E Arbustini, L Vertechy, M De Bonis, S M Boccia, D Giannarelli, V Salutari, M Distefano, M G Ferrandina, C Nero, L Musacchio, A Russo, G Scambia, D Lorusso.
       BACKGROUND: Knowledge about the association between the BRCA1/2 mutation type and location and response to poly (ADP-ribose) polymerase inhibitors (PARPis) as single agent in ovarian cancer is limited. This study aimed to investigate the effectiveness of PARPi based on functional domains (FD) [RING, BRCT, DNA-binding (BD), RAD51-BD] and types (frameshift, missense, nonsense, splicing) of BRCA1/2 gene mutations in ovarian cancer.
    MATERIALS AND METHODS: This multicenter real-world study retrospectively enrolled BRCA1/2-mutated ovarian cancer patients receiving olaparib maintenance between January 2010 and December 2022. Data were compared with historical series of patients who did not receive olaparib and analyzed based on the FD involved in BRCA1/2 mutations. Progression-free survival was calculated from the date of the last platinum-based treatment until recurrence or last follow-up.
    RESULTS: After a median follow-up of 46 months (range 32-60 months), 140 patients who underwent olaparib maintenance were compared with 128 who did not. PARPi showed efficacy in the overall population. The no-exon 11 patients benefitted more from olaparib than exon 11 patients [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.25-0.93]. In the BRCA1 group, patients with mutations in RING and BRCT domains had significant benefits from PARPi (HR 0.08, 95% CI 0.01-0.75; HR 0.10, 95% CI 0.02-0.38, respectively). Among BRCA2-mutated patients, RAD51-BD mutations were associated with higher response to olaparib (HR 0.23, 95% CI 0.10-0.52). According to the mutation type, the major effect of PARPi was in the missense group (HR 0.04, 95% CI 0.01-0.31). No patients with p.(Ala1708Glu) in the BRCT domain (BRCA1) receiving PARPi experienced recurring disease in the study period.
    CONCLUSIONS: BRCA1/2-mutated patients benefit from olaparib, but with variations according to the mutation type and FDs. BRCA1-mutated patients in the RING or BRCT and BRCA2-mutated in the RAD51-BD have the greatest benefit. Patients with missense mutations, especially those with p.(Ala1708Glu), have the most significant advantage from maintenance with PARPi.
    Keywords:  BRCA mutation; PARP inhibitors; mutation site; mutation type; ovarian cancer
    DOI:  https://doi.org/10.1016/j.esmoop.2025.104533
  6. Gynecol Oncol. 2025 Apr 02. pii: S0090-8258(25)00106-4. [Epub ahead of print]196 59-61
    MUTYH: Possibly another important gene in ovarian cancer?
    Roxanna Haghighat, Amanda Laterza Ozarowski, Ying L Liu, Melissa K Frey.
      
    DOI:  https://doi.org/10.1016/j.ygyno.2025.03.029
  7. Nat Commun. 2025 Mar 28. 16(1): 3033
    Cell-cycle dependent DNA repair and replication unifies patterns of chromosome instability.
    Bingxin Lu, Samuel Winnall, William Cross, Chris P Barnes.
      Chromosomal instability (CIN) is pervasive in human tumours and often leads to structural or numerical chromosomal aberrations. Somatic structural variants (SVs) are intimately related to copy number alterations but the two types of variant are often studied independently. Additionally, despite numerous studies on detecting various SV patterns, there are still no general quantitative models of SV generation. To address this issue, we develop a computational cell-cycle model for the generation of SVs from end-joining repair and replication after double-strand break formation. Our model provides quantitative information on the relationship between breakage fusion bridge cycle, chromothripsis, seismic amplification, and extra-chromosomal circular DNA. Given whole-genome sequencing data, the model also allows us to infer important parameters in SV generation with Bayesian inference. Our quantitative framework unifies disparate genomic patterns resulted from CIN, provides a null mutational model for SV, and reveals deeper insights into the impact of genome rearrangement on tumour evolution.
    DOI:  https://doi.org/10.1038/s41467-025-58245-z
  8. Genomics Proteomics Bioinformatics. 2025 Apr 04. pii: qzaf028. [Epub ahead of print]
    Cell-free DNA Fragmentomics Assay to Discriminate the Malignancy of Breast Nodules and Evaluate Treatment Response.
    Jiaqi Liu, Yalun Li, Wanxiangfu Tang, Tianyi Qian, Lijun Dai, Ziqi Jia, Heng Cao, Chenghao Li, Yuchen Liu, Yansong Huang, Jiang Wu, Dongxu Ma, Guangdong Qiao, Hua Bao, Shuang Chang, Dongqin Zhu, Shanshan Yang, Xuxiaochen Wu, Xue Wu, Hengyi Xu, Hongyan Chen, Yang Shao, Xiang Wang, Zhihua Liu, Jianzhong Su.
      The fragmentomics-based cell-free DNA (cfDNA) assays have recently illustrated prominent abilities to identify various cancers from non-conditional healthy controls, while their accuracy for identifying early-stage cancers from benign lesions with inconclusive imaging results remains uncertain. Especially for breast cancer, current imaging-based screening methods suffer from high false positive rates for women with breast nodules, leading to unnecessary biopsies, which add to discomfort and healthcare burden. Here, we enrolled 613 female participants in this multi-center study and demonstrated that cfDNA fragmentomics (cfFrag) is a robust non-invasive biomarker for breast cancer using whole-genome sequencing. Among the multimodal cfFrag profiles, the fragment size ratio (FSR), fragment size distribution (FSD), and copy number variation (CNV) show more distinguishing ability than Griffin, motif breakpoint (MBP), and neomer. The cfFrag model using the optimal three fragmentomics features discriminated early-stage breast cancers from benign nodules, even at a low sequencing depth (3×). Notably, it demonstrated a specificity of 94.1% in asymptomatic healthy women at a 90% sensitivity for breast cancers. Moreover, we comprehensively showcased the clinical utilities of the cfFrag model in predicting patient responses to neoadjuvant chemotherapy (NAC) and in combining with multimodal features, including radiological results and cfDNA methylation features [with area under the curve (AUC) values of 0.93-0.94 and 0.96, respectively].
    Keywords:  Breast cancer; Cell-free DNA methylation; Fragmentomics; Neoadjuvant chemotherapy; Whole-genome sequencing
    DOI:  https://doi.org/10.1093/gpbjnl/qzaf028
  9. Cancer. 2025 Apr 01. 131(7): e35823
    Multicancer early detection testing: Guidance for primary care discussions with patients.
    Richard M Hoffman, Andrew M D Wolf, Sana Raoof, Carmen E Guerra, Timothy R Church, Elena B Elkin, Ruth D Etzioni, Ya-Chen Tina Shih, Steven J Skates, Deana Manassaram-Baptiste, Robert A Smith.
      Multicancer early detection (MCED) tests are an emerging technology for cancer screening. MCED tests can detect cancer signals from multiple cancers concurrently in biological samples such as blood, urine, saliva, or other bodily fluids. Some tests can suggest the most likely cancer origin, whereas others report cancer detected somewhere in the body. Although some MCED tests are currently commercially available, none are approved by the Food and Drug Administration or endorsed by any clinical practice guideline or recommendation. Most insurance companies do not currently cover MCED testing. MCED tests have not yet been evaluated for safety and effectiveness in randomized controlled trials. Because patients already are asking for MCED test prescriptions or for interpretation of results from tests acquired elsewhere, clinicians should be prepared to discuss what is known about the benefits, risks, and uncertainties of MCED testing, including performance characteristics in screening populations and preferred follow-up strategies for positive test results. At this time, clinicians should not feel obligated to initiate discussions about MCED testing with their patients. However, clinicians should engage patients who inquire about getting tested or previous MCED test results in shared decision-making, and take the opportunity to offer and help patients complete age- and sex-appropriate guideline-recommended cancer screenings. In this article, the current evidence and issues around MCED testing are summarized, and a framework for shared decision-making discussions is provided.
    Keywords:  American Cancer Society; United States; humans; mass screening; neoplasms/diagnosis/prevention and control
    DOI:  https://doi.org/10.1002/cncr.35823
  10. N Engl J Med. 2025 Apr 03. pii: 10.1056/NEJMc2501310#sa2. [Epub ahead of print]392(13): 1350
    Cervical Cancer.
    Linda Harris.
      
    DOI:  https://doi.org/10.1056/NEJMc2501310
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒08 at 7:08.