bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023–01–15
eight papers selected by
Sergio Marchini, Humanitas Research
  1. Clinical application of PARP inhibitors in ovarian cancer: from molecular mechanisms to the current status.
  2. Locally Performed HRD Testing for Ovarian Cancer? Yes, We Can!
  3. The role of interferons in ovarian cancer progression: Hinderer or promoter?
  4. The Adaptability of Chromosomal Instability in Cancer Therapy and Resistance.
  5. DNA Methylation: From Cancer Biology to Clinical Perspectives.
  6. ABSP: an automated R tool to efficiently analyze region-specific CpG methylation from bisulfite sequencing PCR.
  7. The emerging roles of γδ T cells in cancer immunotherapy.
  8. Single-cell and spatial sequencing application in pathology.
  1. J Ovarian Res. 2023 Jan 07. 16(1): 6
    Clinical application of PARP inhibitors in ovarian cancer: from molecular mechanisms to the current status.
    Yongsong Wu, Shilin Xu, Shanshan Cheng, Jiani Yang, Yu Wang.
      As a kind of gynecological tumor, ovarian cancer is not as common as cervical cancer and breast cancer, but its malignant degree is higher. Despite the increasingly mature treatment of ovarian cancer, the five-year survival rate of patients is still less than 50%. Based on the concept of synthetic lethality, poly (ADP- ribose) polymerase (PARP) inhibitors target tumor cells with defects in homologous recombination repair(HRR), the most significant being the target gene Breast cancer susceptibility genes(BRCA). PARP inhibitors capture PARP-1 protein at the site of DNA damage to destroy the original reaction, causing the accumulation of PARP-DNA nucleoprotein complexes, resulting in DNA double-strand breaks(DSBs) and cell death. PARP inhibitors have been approved for the treatment of ovarian cancer for several years and achieved good results. However, with the widespread use of PARP inhibitors, more and more attention has been paid to drug resistance and side effects. Therefore, further research is needed to understand the mechanism of PARP inhibitors, to be familiar with the adverse reactions of the drug, to explore the markers of its efficacy and prognosis, and to deal with its drug resistance. This review elaborates the use of PARP inhibitors in ovarian cancer.
    Keywords:  BRCA; Biomarkers; Chemotherapy resistance; Homologous recombination repair; Ovarian cancer; PARP inhibitor; Side effect; Synthetic lethality
    DOI:  https://doi.org/10.1186/s13048-023-01094-5
  2. Cancers (Basel). 2022 Dec 21. pii: 43. [Epub ahead of print]15(1):
    Locally Performed HRD Testing for Ovarian Cancer? Yes, We Can!
    Gilda Magliacane, Emanuela Brunetto, Silvia Calzavara, Alice Bergamini, Giovanni Battista Pipitone, Giovanna Marra, Miriam Redegalli, Greta Grassini, Emanuela Rabaiotti, Gianluca Taccagni, Lorenza Pecciarini, Paola Carrera, Giorgia Mangili, Claudio Doglioni, Maria Giulia Cangi.
      Assessment of HRD status is now essential for ovarian cancer patient management. A relevant percentage of high-grade serous carcinoma (HGSC) is characterized by HRD, which is caused by genetic alterations in the homologous recombination repair (HRR) pathway. Recent trials have shown that not only patients with pathogenic/likely pathogenic BRCA variants, but also BRCAwt/HRD patients, are sensitive to PARPis and platinum therapy. The most common HRD test is Myriad MyChoice CDx, but there is a pressing need to offer an alternative to outsourcing analysis, which typically requires high costs and lengthy turnaround times. In order to set up a complete in-house workflow for HRD testing, we analyzed a small cohort of HGSC patients using the CE-IVD AmoyDx HRD Focus Panel and compared our results with Myriad's. In addition, to further deepen the mechanisms behind HRD, we analyzed the study cohort by using both a custom NGS panel that analyzed 21 HRR-related genes and FISH analysis to determine the copy numbers of PTEN and EMSY. We found complete concordance in HRD status detected by the Amoy and the Myriad assays, supporting the feasibility of internal HRD testing.
    Keywords:  BRCA; HRD; HRR; NGS; PARPi; molecular testing; ovarian cancer
    DOI:  https://doi.org/10.3390/cancers15010043
  3. Front Immunol. 2022 ;13 1087620
    The role of interferons in ovarian cancer progression: Hinderer or promoter?
    Taiqing Liu, Yinqi Li, Xiaoyu Wang, Xiaodong Yang, Yunhai Fu, Yeteng Zheng, Hanlin Gong, Zhiyao He.
      Ovarian cancer (OC) is a common gynecologic malignancy with poor prognosis and high mortality. Changes in the OC microenvironment are closely related to the genesis, invasion, metastasis, recurrence, and drug-resistance. The OC microenvironment is regulated by Interferons (IFNs) known as a type of important cytokines. IFNs have a bidirectional regulation for OC cells growth and survival. Meanwhile, IFNs positively regulate the recruitment, differentiation and activation of immune cells. This review summarizes the secretion and the role of IFNs. In particular, we mainly elucidate the actions played by IFNs in various types of therapy. IFNs assist radiotherapy, targeted therapy, immunotherapy and biotherapy for OC, except for some IFN pathways that may cause chemo-resistance. In addition, we present some advances in OC treatment with the help of IFN pathways. IFNs have the ability to powerfully modulate the tumor microenvironment and can potentially provide new combination strategies for OC treatment.
    Keywords:  biotherapy; immune cell; immunotherapy; interferons; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.1087620
  4. Int J Mol Sci. 2022 Dec 23. pii: 245. [Epub ahead of print]24(1):
    The Adaptability of Chromosomal Instability in Cancer Therapy and Resistance.
    Vinicio Carloni, Elisa Morganti, Andrea Galli, Antonio Mazzocca.
      Variation in chromosome structure is a central source of DNA damage and DNA damage response, together representinga major hallmark of chromosomal instability. Cancer cells under selective pressure of therapy use DNA damage and DNA damage response to produce newfunctional assets as an evolutionary mechanism. Recent efforts to understand DNA damage/chromosomal instability and elucidate its role in initiation or progression of cancer have also disclosed its vulnerabilities represented by inappropriate DNA damage response, chromatin changes, andinflammation. Understanding these vulnerabilities can provide important clues for predicting treatment response and for the development of novel strategies that prevent the emergence of therapy resistant tumors.
    Keywords:  DNA damage; DNA damage response; epigenetic changes; immune evasion; immunotherapy
    DOI:  https://doi.org/10.3390/ijms24010245
  5. Front Biosci (Landmark Ed). 2022 12 20. 27(12): 326
    DNA Methylation: From Cancer Biology to Clinical Perspectives.
    Chen Chen, Zehua Wang, Yi Ding, Lei Wang, Siyuan Wang, Haonan Wang, Yanru Qin.
      DNA methylation plays an important role in the silence of tissue-specific genes to prevent them from being expressed in the wrong tissue. Aberrant DNA methylation (genome-wide hypomethylation and site-specific hypermethylation) are observed in many types of cancer. DNA methylation patterns are established and maintained through the combined actions of methyltransferase and demethylase, such as DNA methyltransferase (DNMT)-1, DNMT-3, and ten-eleven translocation (TET) family enzymes. It is well known that the process of tumor evolution is complicated with different hallmarks. Early findings put forward the model that focal hypermethylation of tumor suppressor genes (TSG) could straightly trigger transcriptional silencing and malignant transformation, whereas varying levels of DNA methylation also occur at other sites and can differently regulate gene expression and biological processes. The interplay of tumor and immune cells in the tumor microenvironment is complex. Understanding the role of DNA methylation in cancer immunity is critical to better navigate epigenetic agents. Furthermore, a greater understanding of the interaction of DNA methylation with tumor metabolic reprogramming would create a bright avenue for pharmacologic managements of malignancies. In this review, we will describe the molecular mechanisms of DNA methylation abnormalities in cancer biology, introduce the roles of DNA methylation patterns on cancer-immunity cycle and metabolic reprogramming, summarize modulators that are used in targeting DNA remodeling, and highlight the importance of combining epigenome-targeting drugs with other cancer therapies.
    Keywords:  DNA methylation; cancer-immunity; metabolism reprogramming; novel anti-cancer strategy
    DOI:  https://doi.org/10.31083/j.fbl2712326
  6. Bioinformatics. 2023 Jan 11. pii: btad008. [Epub ahead of print]
    ABSP: an automated R tool to efficiently analyze region-specific CpG methylation from bisulfite sequencing PCR.
    Marie Denoulet, Mathilde Brulé, François Anquez, Audrey Vincent, Julie Schnipper, Eric Adriaenssens, Robert-Alain Toillon, Xuefen Le Bourhis, Chann Lagadec.
       MOTIVATION: Nowadays, epigenetic gene regulations are studied in each part of the biology, from embryonic development to diseases such as cancers and neurodegenerative disorders. Currently, to quantify and compare CpG methylation levels of a specific region of interest, the most accessible technique is the Bisulfite Sequencing PCR (BSP). However, no existing user-friendly tool is able to analyze data from all approaches of BSP. Therefore, the most convenient way to process results from the direct sequencing of PCR products (direct-BSP) is to manually analyze the chromatogram traces, which is a repetitive and prone to error task.
    RESULTS: Here, we implement a new R-based tool, called ABSP for Analysis of Bisulfite Sequencing PCR, providing a complete analytic process of both direct-BSP and cloning-BSP data. It uses the raw sequencing trace files (.ab1) as input to compute and compare CpG methylation percentages. It is fully automated and includes a user-friendly interface as a built-in R shiny app, quality control steps, and generates publication-ready graphics.
    AVAILABILITY AND IMPLEMENTATION: The ABSP tool and associated data are available on GitHub at https://github.com/ABSP-methylation-tool/ABSP.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btad008
  7. Nat Rev Clin Oncol. 2023 Jan 09.
    The emerging roles of γδ T cells in cancer immunotherapy.
    Sofia Mensurado, Rafael Blanco-Domínguez, Bruno Silva-Santos.
      Current cancer immunotherapies are primarily predicated on αβ T cells, with a stringent dependence on MHC-mediated presentation of tumour-enriched peptides or unique neoantigens that can limit their efficacy and applicability in various contexts. After two decades of preclinical research and preliminary clinical studies involving very small numbers of patients, γδ T cells are now being explored as a viable and promising approach for cancer immunotherapy. The unique features of γδ T cells, including their tissue tropisms, antitumour activity that is independent of neoantigen burden and conventional MHC-dependent antigen presentation, and combination of typical properties of T cells and natural killer cells, make them very appealing effectors in multiple cancer settings. Herein, we review the main functions of γδ T cells in antitumour immunity, focusing on human γδ T cell subsets, with a particular emphasis on the differences between Vδ1+ and Vδ2+ γδ T cells, to discuss their prognostic value in patients with cancer and the key therapeutic strategies that are being developed in an attempt to improve the outcomes of these patients.
    DOI:  https://doi.org/10.1038/s41571-022-00722-1
  8. J Pathol Transl Med. 2023 Jan 10.
    Single-cell and spatial sequencing application in pathology.
    Yoon-Seob Kim, Jinyong Choi, Sug Hyung Lee.
      Traditionally, diagnostic pathology uses histology representing structural alterations in a disease's cells and tissues. In many cases, however, it is supplemented by other morphology-based methods such as immunohistochemistry and fluorescent in situ hybridization. Single-cell RNA sequencing (scRNA-seq) is one of the strategies that may help tackle the heterogeneous cells in a disease, but it does not usually provide histologic information. Spatial sequencing is designed to assign cell types, subtypes, or states according to the mRNA expression on a histological section by RNA sequencing. It can provide mRNA expressions not only of diseased cells, such as cancer cells but also of stromal cells, such as immune cells, fibroblasts, and vascular cells. In this review, we studied current methods of spatial transcriptome sequencing based on their technical backgrounds, tissue preparation, and analytic procedures. With the pathology examples, useful recommendations for pathologists who are just getting started to use spatial sequencing analysis in research are provided here. In addition, leveraging spatial sequencing by integration with scRNA-seq is reviewed. With the advantages of simultaneous histologic and single-cell information, spatial sequencing may give a molecular basis for pathological diagnosis, improve our understanding of diseases, and have potential clinical applications in prognostics and diagnostic pathology.
    Keywords:  Diseases; Histology; Pathology; Single-cell sequencing; Spatial sequencing; Transcriptome
    DOI:  https://doi.org/10.4132/jptm.2022.12.12
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