bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2024–12–29
six papers selected by
Sergio Marchini, Humanitas Research



  1. Comput Struct Biotechnol J. 2024 Dec;23 4369-4383
      The rapid development of spatial transcriptomics (ST) technology has provided unprecedented opportunities to understand tissue relationships and functions within specific spatial contexts. Accurate identification of spatial domains is crucial for downstream spatial transcriptomics analysis. However, effectively combining gene expression data, histological images and spatial coordinate data to identify spatial domains remains a challenge. To this end, we propose STMVGAE, a novel spatial transcriptomics analysis tool that combines a multi-view variational graph autoencoder with a consensus clustering framework. STMVGAE begins by extracting histological images features using a pre-trained convolutional neural network (CNN) and integrates these features with gene expression data to generate augmented gene expression profiles. Subsequently, multiple graphs (views) are constructed using various similarity measures, capturing different aspects of the spatial and transcriptional relationships. These views, combined with the augmented gene expression data, are then processed through variational graph auto-encoders (VGAEs) to learn multiple low-dimensional latent embeddings. Finally, the model employs a consensus clustering method to integrate the clustering results derived from these embeddings, significantly improving clustering accuracy and stability. We applied STMVGAE to five real datasets and compared it with five state-of-the-art methods, showing that STMVGAE consistently achieves competitive results. We assessed its capabilities in spatial domain identification and evaluated its performance across various downstream tasks, including UMAP visualization, PAGA trajectory inference, spatially variable gene (SVG) identification, denoising, batch integration, and other analyses. All code and public datasets used in this paper is available at https://github.com/wenwenmin/STMVGAE and https://zenodo.org/records/13119867.
    Keywords:  Consensus clustering; Deep learning; Multi-view variational graph autoencoders; Spatially resolved transcriptomics
    DOI:  https://doi.org/10.1016/j.csbj.2024.11.041
  2. Trends Cell Biol. 2024 Dec 26. pii: S0962-8924(24)00249-6. [Epub ahead of print]
      Technical advances over the past two decades have enabled robust detection of cell-free DNA (cfDNA) in biological samples. Yet, higher clinical sensitivity is required to realize the full potential of liquid biopsies. This opinion article argues that to overcome current limitations, the abundance of informative cfDNA molecules - such as circulating tumor DNA (ctDNA) - collected in a sample needs to increase. To accomplish this, new methods to modulate the biological processes that govern cfDNA production, trafficking, and clearance in the body are needed, informed by a deeper understanding of cfDNA biology. Successful development of such methods could enable a major leap in the performance of liquid biopsies and vastly expand their utility across the spectrum of clinical care.
    Keywords:  biomarkers; cfDNA clearance; cfDNA shedding; ctDNA
    DOI:  https://doi.org/10.1016/j.tcb.2024.11.007
  3. Clin Cancer Res. 2024 Dec 26.
      A companion diagnostic is a diagnostic test that provides information essential for the safe and effective use of a corresponding therapeutic product. To obtain marketing approval, the companion diagnostic must demonstrate acceptable analytical and clinical performance. Companion diagnostic regulations are intended to protect patients by ensuring quality and consistency of treatment-guiding biomarker testing in clinical trials and clinical practice. However, current regulations have had unintended negative consequences relating to innovation, implementation and accessibility of precision medicine, increasing complexity and cost burden as well as inhibiting development of novel diagnostics and biomarker-targeted therapeutics. We propose a range of practical solutions to these challenges, advocating that regulators, pharmaceutical companies, molecular pathologist groups and diagnostics companies work together to increase flexibility and promote diagnostic innovation, whilst maintaining high quality diagnostic testing to ensure all patients get the most appropriate treatments.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2729
  4. Curr Oncol. 2024 Dec 20. 31(12): 8054-8074
      The enzyme topoisomerase II alpha (TOP2A) plays a critical role in DNA replication and cell proliferation, making it a promising target for cancer therapy. In epithelial ovarian cancer (EOC), TOP2A overexpression is associated with poor prognosis and resistance to conventional treatments. This review explores the biological functions of TOP2A in EOC and discusses its potential as a therapeutic target. We highlight studies on the mechanisms through which TOP2A contributes to tumor progression and recurrence. Additionally, we evaluate the clinical implications of targeting TOP2A, including the use of TOP2A inhibitors and their combination with novel drugs. We provide a comprehensive overview of the current understanding and future directions for targeting TOP2A in the management of EOC.
    Keywords:  PARPi; TOP2A; anthracyclines; doxorubicin; etoposide; immune checkpoint inhibitors; ovarian cancer; topoisomerase
    DOI:  https://doi.org/10.3390/curroncol31120594
  5. BMC Cancer. 2024 Dec 22. 24(1): 1565
       BACKGROUND: Epithelial ovarian cancer (EOC) is a lethal form of gynecological malignancy. Some EOC patients experience relapse after standard primary debulking surgery (PDS) and adjuvant chemotherapy (ACT). Identifying molecular residual disease (MRD) by circulating tumor DNA (ctDNA) detection can timely signal the potential for relapse. However, research on the usage of ctDNA for MRD detection in EOC is limited.
    METHODS: Fifty-one EOC patients who received standard PDS and ACT were included. Targeted sequencing based on a panel of 1021 cancer-related genes, along with further validation using Enrich-rare-mutation sequencing, was performed on tumor tissues acquired during PDS and on plasma samples collected before and after PDS/ACT to identify variants reflecting tumor signals.
    RESULTS: Post-surgery MRD was associated with relapse (Log-rank p = 0.0006) and was identified as an independent prognostic factor (HR, 3.4; 95% CI, 1.02-11.42; p = 0.047). The negative and positive predictive values were 0.83 and 0.62 respectively. Additionally, post-surgery MRD outperformed CA125 in predicting relapse, and integrating both parameters could provide more accurate risk stratification. Post-ACT MRD detection identified the patients with ctDNA clearance who were still at risk of relapse. Furthermore, baseline ctDNA detection could help determine patients who are not suitable for further tests after surgery.
    CONCLUSIONS: Post-surgery MRD is superior to CA125 in predicting relapse in EOC. Patients exhibiting transient ctDNA clearance, as evaluated by post-ACT MRD, may require longitudinal monitoring. Baseline ctDNA detection could help determine whether post-surgery ctDNA monitoring should be performed.
    Keywords:  CA125; Circulating tumor DNA; Epithelial ovarian cancer; Molecular residual disease; Relapse
    DOI:  https://doi.org/10.1186/s12885-024-13222-5
  6. Int J Cancer. 2024 Dec 22.
      Genetic mutations are well known to influence tumorigenesis, tumor progression, treatment response and relapse, but the role of epigenetic variation in cancer progression is still largely unexplored. The lack of epigenetic understanding in cancer evolution is in part due to the limited availability of methods to examine such a heterogeneous disease. However, in the last decade the development of several single-cell methods to profile diverse chromatin features (chromatin accessibility, histone modifications, DNA methylation, etc.) has propelled the study of cancer epigenomics. In this review, we detail the current landscape of single-omic and multi-omic single-cell methods with a particular focus on the examination of histone modifications. Furthermore, we provide recommendations on both the application of these methods to cancer research and how to perform initial computational analyses. Together, this review serves as a referential framework for incorporating single-cell methods as an important tool for tumor biology.
    Keywords:  cancer; chromatin; histone modifications; single‐cell epigenomics; tumor heterogeneity
    DOI:  https://doi.org/10.1002/ijc.35307