bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2021–09–05
seven papers selected by
Lara Paracchini, Humanitas Research
  1. Cell-free DNA is abundant in ascites and represents a liquid biopsy of ovarian cancer.
  2. Size Distribution of Cell-free DNA in Oncology.
  3. Immune microenvironment composition in high-grade serous ovarian cancers based on BRCA mutational status.
  4. Liquid biopsy for cancer detection: Clinical and epidemiological considerations.
  5. Single-cell transcriptomes reveal heterogeneity of high-grade serous ovarian carcinoma.
  6. EpiScanpy: integrated single-cell epigenomic analysis.
  7. Genome-wide sequencing of cell-free DNA enables detection of copy number alterations in cancer patients where tissue biopsy is not feasible.
  1. Gynecol Oncol. 2021 Sep;pii: S0090-8258(21)00524-2. [Epub ahead of print]162(3): 720-727
    Cell-free DNA is abundant in ascites and represents a liquid biopsy of ovarian cancer.
    INOVATe Investigators
       OBJECTIVE: Malignant ascites is a common clinical feature of ovarian cancer and represents a readily accessible sample of tumour cells and tumour DNA. This study aimed to characterise the cell-free DNA (cfDNA) in ascites in terms of its size profile, stability and cell-free tumour DNA (cftDNA) content.
    METHODS: Cell spheroids, loose cells and cell-free fluid was collected from ascites from 18 patients with ovarian cancer. cfDNA was isolated and assessed for size by electrophoresis, concentration by fluorometry,cftDNA content by methylation specific qPCR of HOXA9 and IFFO1 promoter regions and by targeted sequencing. Stability was assessed after ascites fluid was stored at 4 °C for 24 and 72 h before fractionating.
    RESULTS: The concentration of cfDNA in ascites ranged from 6.6 to 300 ng/mL. cfDNA size distribution resembled blood plasma-derived cfDNA, with major peaks corresponding to mono- and di-nucleosome DNA fragments. High molecular weight cfDNA was observed in 7 of 18 patients and appeared to be associated with extracellular vesicles. IFFO1 and HOXA9 methylation was proportionately higher in cfDNA than spheroid- and loose-cell fractions and was not observed in healthy primary cells. Variant allele frequency was highest in cfDNA compared to single cells and spheroids from ascites. Though cancer cell numbers in ascites declined to near zero in recurrent ascites from one patient undertaking chemotherapy, cftDNA could still be sampled. cfDNA size, concentration and tumour content was stable over 72 h.
    CONCLUSION: cfDNA in ovarian cancer ascites demonstrates inter-patient variability, yet is consistently a rich source of cftDNA, which is a stable substrate. This supports the wider clinical use of ascites in the molecular analysis of ovarian cancer.
    Keywords:  Ascites; Cell-free DNA; Extracellular vesicles; IFFO1; Methylation-specific qPCR; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.ygyno.2021.06.028
  2. Crit Rev Oncol Hematol. 2021 Aug 28. pii: S1040-8428(21)00243-2. [Epub ahead of print] 103455
    Size Distribution of Cell-free DNA in Oncology.
    Sasimol Udomruk, Santhasiri Orrapin, Dumnoensun Pruksakorn, Parunya Chaiyawat.
      Tumor-specific, circulating cell-free DNA (cfDNA) in liquid biopsy test is a novel promising biomarker in the advancement of cancer management, including early diagnosis, screening, prognosis, identification of actionable targets, and serial tumor monitoring. The specific size pattern of DNA fragments derived from cancer cells is observed to differ from that of cfDNA fragments shed by non-cancer cells. Research into the physiological and biological properties of cfDNA reveals the molecular signature carried by each cfDNA fragments, which can reflect their tissue origins, as well as the mutational profiles with significant genetic alterations. Understanding the fragmentation and size distribution of cfDNA might be a valuable hotspot in liquid biopsy research, with the potential to drive innovation in oncology.
    Keywords:  Cancer; Cell-free DNA; Circulating tumor DNA; Fragment size distribution; Liquid biopsy; Mutation allele frequency
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103455
  3. J Cancer Res Clin Oncol. 2021 Sep 02.
    Immune microenvironment composition in high-grade serous ovarian cancers based on BRCA mutational status.
    Sara Corvigno, Jared K Burks, Wei Hu, Yanping Zhong, Nicholas B Jennings, Nicole D Fleming, Shannon N Westin, Bryan Fellman, Jinsong Liu, Anil K Sood.
       PURPOSE: An in-depth analysis of the tumor microenvironment of ovarian cancer is needed. The purpose of this study was to elucidate the architecture of the immune microenvironment of high-grade serous ovarian cancers (HGSCs) with or without BRCA1 and BRCA2 mutations.
    METHODS: A cohort of highly annotated HGSC patients with known germline BRCA1 and BRCA2 status was selected, and pretreatment tumor tissue specimens were analyzed with a multiplexed staining technique aimed at detecting lymphocytes, macrophages, and fibroblasts in the whole tumor area and in specific regions including epithelium, stroma, and perivascular areas.
    RESULTS: BRCA1- or BRCA2-mutated tumors showed a more immunogenic microenvironment, characterized by a higher abundance of CD8+ and PD-L1+ cells, than did tumors with wild-type BRCA1 and BRCA2. High numbers of PD-L1+ and PD-L1+CD8+ cells were prognostic for event-free survival (hazard ratio [HR]: 0.41, 95% CI 0.21-0.79, p = 0.008 and HR 0.49, 95% CI 0.26-0.91, p = 0.025, respectively), as were high numbers of epithelial PD-L1+ and FAP+PD-L1+ cells (HR 0.52, 95% CI 0.28-0.96, p = 0.037 and HR 0.27, 95% CI 0.08-0.87, p = 0.029) and CD8+ cells (HR 0.51, 95% CI 0.28-0.93, p = 0.027).
    CONCLUSIONS: This study reveals substantial differences between the immune microenvironment composition of germline BRCA-mutated and BRCA wild-type HGSC.
    Keywords:  BRCA; Fibroblasts; Immune cells; Lymphocytes; Multiple staining; Serous ovarian cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00432-021-03778-1
  4. Clin Cancer Res. 2021 Aug 30. pii: clincanres.2426.2021. [Epub ahead of print]
    Liquid biopsy for cancer detection: Clinical and epidemiological considerations.
    Nicolas Wentzensen, Megan A Clarke.
      Detection of circulating nucleic acids, also referred to as liquid biopsy, has been evaluated for detection of cancer in a variety of settings. We describe important clinical and epidemiological considerations for liquid biopsy applications in cancer early detection and for monitoring of cancer recurrence.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-2426
  5. Clin Transl Med. 2021 Aug;11(8): e500
    Single-cell transcriptomes reveal heterogeneity of high-grade serous ovarian carcinoma.
    Qian Hao, Jiajia Li, Qinghua Zhang, Fei Xu, Bangxiang Xie, Hua Lu, Xiaohua Wu, Xiang Zhou.
       BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive histotype of epithelial ovarian cancer. The heterogeneity and molecular basis of this disease remain incompletely understood.
    METHODS: To address this question, we have performed a single-cell transcriptomics analysis of matched primary and metastatic HGSOC samples.
    RESULTS: A total of 13 571 cells are categorized into six distinct cell types, including epithelial cells, fibroblast cells, T cells, B cells, macrophages, and endothelial cells. A subset of aggressive epithelial cells with hyperproliferative and drug-resistant potentials is identified. Several new markers that are highly expressed in epithelial cells are characterized, and their roles in ovarian cancer cell growth and migration are further confirmed. Dysregulation of multiple signaling pathways, including the translational machinery, is associated with ovarian cancer metastasis through the trajectory analysis. Moreover, single-cell regulatory network inference and clustering (SCENIC) analysis reveals the gene regulatory networks and suggests the JUN signaling pathway as a potential therapeutic target for treatment of ovarian cancer, which is validated using the JUN/AP-1 inhibitor T-5224. Finally, our study depicts the epithelial-fibroblast cell communication atlas and identifies several important receptor-ligand complexes in ovarian cancer development.
    CONCLUSIONS: This study uncovers new molecular features and the potential therapeutic target of HGSOC, which would advance the understanding and treatment of the disease.
    Keywords:  chemoresistance; gene regulatory network; intercellular communication; metastasis; single-cell RNA-seq
    DOI:  https://doi.org/10.1002/ctm2.500
  6. Nat Commun. 2021 Sep 01. 12(1): 5228
    EpiScanpy: integrated single-cell epigenomic analysis.
    Anna Danese, Maria L Richter, Kridsadakorn Chaichoompu, David S Fischer, Fabian J Theis, Maria Colomé-Tatché.
      EpiScanpy is a toolkit for the analysis of single-cell epigenomic data, namely single-cell DNA methylation and single-cell ATAC-seq data. To address the modality specific challenges from epigenomics data, epiScanpy quantifies the epigenome using multiple feature space constructions and builds a nearest neighbour graph using epigenomic distance between cells. EpiScanpy makes the many existing scRNA-seq workflows from scanpy available to large-scale single-cell data from other -omics modalities, including methods for common clustering, dimension reduction, cell type identification and trajectory learning techniques, as well as an atlas integration tool for scATAC-seq datasets. The toolkit also features numerous useful downstream functions, such as differential methylation and differential openness calling, mapping epigenomic features of interest to their nearest gene, or constructing gene activity matrices using chromatin openness. We successfully benchmark epiScanpy against other scATAC-seq analysis tools and show its outperformance at discriminating cell types.
    DOI:  https://doi.org/10.1038/s41467-021-25131-3
  7. Mol Cancer Ther. 2021 Aug 31. pii: molcanther.1066.2020. [Epub ahead of print]
    Genome-wide sequencing of cell-free DNA enables detection of copy number alterations in cancer patients where tissue biopsy is not feasible.
    Taylor J Jensen, Aaron M Goodman, Christopher K Ellison, Kimberly A Holden, Shumei Kato, Lisa Kim, Gregory A Daniels, Kerry Fitzgerald, Erin McCarthy, Prachi Nakashe, Amin R Mazloom, Eyad Almasri, Graham McLennan, Daniel S Grosu, Marcia Eisenberg, Razelle Kurzrock.
      When tissue biopsy is not medically prudent or tissue is insufficient for molecular testing, alternative methods are needed. Since cell-free DNA (cfDNA) has been shown to provide a representative surrogate for tumor tissue, we sought to evaluate its utility in this clinical scenario. cfDNA was isolated from the plasma of patients and assayed with low-coverage (~0.3X), genome-wide sequencing. Copy number alterations (CNAs) were identified and characterized using analytical methods originally developed for noninvasive prenatal testing (NIPT) and quantified using the genomic instability number (GIN), a metric that reflects the quantity and magnitude of CNAs across the genome. The technical variability of the GIN was first evaluated in an independent cohort comprising genome-wide sequencing results from 27,754 women who consented to have their samples used for research and whose NIPT results yielded no detected CNAs to establish a detection threshold. Subsequently, cfDNA sequencing data from 96 patients with known cancers but for whom a tissue biopsy could not be obtained are presented. An elevated GIN was detected in 35% of patients and detection rates varied by tumor origin. Collectively, CNAs covered 96.6% of all autosomes. Survival was significantly reduced in patients with an elevated GIN relative to those without. Overall, these data provide a proof-of-concept for the use of low coverage, genome-wide sequencing of cfDNA from cancer patients in order to obtain relevant molecular information in instances where tissue is difficult to access. These data may ultimately serve as an informative complement to other molecular tests.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-1066
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