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Liquid biopsy has gained attention in oncology as a non-invasive diagnostic tool, offering valuable insights into tumor biology through the analysis of circulating nucleic acid (cfDNA and cfRNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and tumor-educated platelets (TEPs). In this review, we summarize the clinical use of liquid biopsies in cancer now and look forward to its future, with a particular emphasis on some the methods used to isolate the liquid biopsy analytes. This technique provides real-time information on tumor dynamics, treatment response, and disease progression, with the potential for early diagnosis and personalized treatment. Despite its advantages, liquid biopsy faces several challenges, particularly in detecting analytes in early-stage cancers and evaluating the tumor molecular fraction. Tumor burden, molecular fraction, and the presence of subclones can impact the sensitivity and specificity of the analysis. Recent advancements in artificial intelligence (AI) have enhanced the diagnostic accuracy of liquid biopsy by integrating data, and multimodal approaches that combine multiple biomarkers such as ctDNA, CTCs, EVs, and TEPs show promise in providing a more comprehensive view of tumor characteristics. Liquid biopsy has the potential to revolutionize cancer care by providing rapid, non-invasive, and cost-effective diagnostics, enabling timely interventions and personalized treatment strategies.

The plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA gene involved in human disease, mainly in cancer onset/progression. Although widely analysed, its biological roles need to be further clarified. Notably, functional studies on PVT1 are complicated by the occurrence of multiple transcript variants, linear and circular, which generate technical issues in the experimental procedures used to evaluate its impact on human disease. Among the many PVT1 transcripts, the linear PVT1 (lncPVT1) and the circular hsa_circ_0001821 (circPVT1) are frequently reported to perform similar pathologic and pro-tumorigenic functions when overexpressed. The stimulation of cell proliferation, invasion and drug resistance, cell metabolism regulation, and apoptosis inhibition is controlled through multiple targets, including MYC, p21, STAT3, vimentin, cadherins, the PI3K/AKT, HK2, BCL2, and CASP3. However, some of this evidence may originate from an incorrect evaluation of these transcripts as two separate molecules, as they share the lncPVT1 exon-2 sequence. We here summarise lncPVT1/circPVT1 functions by mainly focusing on shared pathways, pointing out the potential bias that may exist when the biological role of each transcript is analysed. These considerations may improve the knowledge about lncPVT1/circPVT1 and their specific targets, which deserve further studies due to their diagnostic, prognostic, and therapeutic potential.

Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs.

Colorectal cancer (CRC) is the second most frequently diagnosed cancer worldwide and represents a major challenge for public health. Despite advances in molecular profiling, important gaps remain in our understanding of tumorigenesis and the regulatory mechanisms underlying CRC progression. The most widely adopted classification system is the Consensus Molecular Subtypes (CMS), which stratifies CRC into four biologically distinct subtypes. We investigated the role of A-to-I RNA editing across CMS subtypes in a cohort of 100 CRC patients at various disease stages. Bulk RNA-seq data were analyzed using REDItools to detect editing events, focusing on both recoding sites and edits within repetitive elements, such as Alu sequences. Furthermore, expression levels of the ADAR enzyme family were assessed, and deconvolution analyses were performed on single-cell RNA-seq data from an independent cohort of stage II CRC patients to characterize editing activity within the tumor microenvironment (TME). Competitive endogenous RNA (ceRNA) networks, specific to each CMS subtype, were constructed based on editing events in repetitive elements. A multivariate Cox proportional hazards model was applied to evaluate associations with overall survival (OS). We observed statistically significant differences in ADARB1 expression across CMS subtypes. Single-cell RNA-seq data revealed subtype-specific distribution patterns of ADAR enzymes within the TME. Analysis of editing events showed subtype-specific signatures in both known cancer-related genes (e.g., COPA , CADPS , IGFBP7 ) and novel candidates ( ZNF552 , RALGPS1 ). Editing in repetitive elements informed the construction of distinct ceRNA networks for each CMS subtype, suggesting different post-transcriptional regulatory mechanisms. Survival analysis identified three variables significantly associated with OS, independent of CMS classification and clinical stage: ADARB1 expression, and editing events in NOP14-AS1 (chr4:2960236; p  = 0.036; HR = 0.0069), previously linked to 5-FU sensitivity, and ST7-AS2 (chr4:117120557). This study underscores the biological relevance of RNA editing in CRC, highlighting its impact on chemoresistance, the tumor microenvironment, and subtype-specific gene regulation. Our findings suggest that RNA editing represents a critical post-transcriptional regulatory layer in CRC and holds potential as a biomarker and therapeutic target.

In the original version of this Article, the affiliation details for Giovanni Martinelli were incorrectly given as ‘Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy’ and it should have been given as ‘Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy and not Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy.’Furthermore, the original version of this Article contained an error in the spelling of the authors Alberto L′Abbate and Pietro D′Addabbo, an acute accent was used instead of an apostrophe for these authors names.These errors have now been corrected in both the PDF and HTML versions of the Article.