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Circulating Cell-Free Nucleic Acids and Cancers 2.0
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Circulating Cell-Free Nucleic Acids and Cancers 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 25 May 2024 | Viewed by 9798

Special Issue Editor

Dr. Bruna Scaggiante

E-Mail Website
Guest Editor
Department of Life Sciences, University of Trieste, Giorgeri 1, 34127 Trieste, Italy
Interests: biological fluids; cancer; cancer biomarkers; cfDI; cfDNA; cfNA; copy number variation; ctDNA; ddPCR; disease-free survival; epigenetic; epigenetic sequencing; exosome; extracellular vesicle; genotyping; liquid biopsy; miRNA; mRNA; mutation; ncRNA; next- generation sequencing; overall survival; progression-free survival; recurrence-free survival; whole-exome sequencing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Improvements in the molecular diagnosis and prognosis of cancer and better evaluation of the therapeutic intervention are urgently needed to offer more personalized treatment to patients.

In this respect, the liquid biopsy has great potential for precision medicine, especially for solid tumors: It is applicable for screening, diagnosis, prognosis, and for the predictive value and monitoring of the disease. Liquid biopsy is a versatile and minimally invasive procedure and the availability of high-throughput technologies allows the analysis of very small quantities of targets.

In a liquid biopsy, the targeting of circulating cell-free nucleic acids (cfNA), is one of the most interesting aspects because many cancer biomarkers, already identified in the tissue, can be found in circulating cell-free DNA (cfDNA). In cfDNA, a fraction of tumor DNA (ctDNA) can be searched by identifying both the cancer-related mutations and the copy number variation of specific genes. The cancer-related methylation status of selected genes in cfDNA can also be measured. Moreover, it has been demonstrated that ctDNA quantity can be related to the integrity index of the cfDNA, (cfDI), i.e., the fraction of long over short-nested fragments of the same DNA target. Many studies indicate that ctDNA analysis can depict tumor heterogeneity. Recently, the role of circulating-free RNA molecules (cfRNA) in diagnosis, prognosis, and therapy responsiveness is emerging. In general, studies on cfNA have a high translational potential for clinical practice, as in EGFR mutations validated by FDA in 2016 for NSCLC. Finally, the analysis of cfNA has the advantage of being highly specific but simpler and lower costing than analyses using circulating tumor cells. Thus, they can be useful to facilitate therapeutic decision-making and to predict tumor burden after therapies or the acquired treatment resistance.

Topics of interest for this Special Issue include but are not limited to the following:

  • Liquid biopsy targeting cfNA for cancer molecular diagnostic
  • Clinical validity and utility of cfNA analysis for tumors
  • Epigenetic markers for cancer by liquid biopsy
  • Extracellular Vesicle biomarkers in liquid biopsy
  • New insights in cfNA biomarkers (cfDNA, ctDNA, cfDI and cfRNA) for screening, diagnosis, prognosis, follow-up and therapeutic management of tumors
  • New techniques to evaluate cfNA
  • Liquid biopsy on Exosome for cancer diagnostic

Dr. Bruna Scaggiante
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • biological fluids
  • cancer
  • cancer biomarkers
  • cfDI
  • cfDNA
  • cfNA
  • Copy number variation
  • ctDNA
  • ddPCR
  • disease-free survival
  • epigenetic
  • epigenetic sequencing
  • exosome
  • extracellular vesicle
  • genotyping
  • liquid biopsy
  • miRNA
  • mRNA
  • mutation
  • ncRNA
  • next-generation sequencing
  • overall survival
  • progression-free survival
  • recurrence-free survival
  • whole-exome sequencing

Published Papers (6 papers)

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Research

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14 pages, 1675 KiB  
Article
Correlation between Circulating miR-16, miR-29a, miR-144 and miR-150, and the Radiotherapy Response and Survival of Non-Small-Cell Lung Cancer Patients
by Matthias Bache, Frauke Kadler, Olivia Struck, Daniel Medenwald, Christian Ostheimer, Antje Güttler, Jacqueline Keßler, Matthias Kappler, Anne Riemann, Oliver Thews, Barbara Seliger and Dirk Vordermark
Int. J. Mol. Sci. 2023, 24(16), 12835; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612835 - 16 Aug 2023
Cited by 1 | Viewed by 1056
Abstract
Despite the success of current therapy concepts, patients with advanced non-small-cell lung cancer (NSCLC) still have a very poor prognosis. Therefore, biological markers are urgently needed, which allow the assessment of prognosis, or prediction of the success of therapy or resistance in this [...] Read more.
Despite the success of current therapy concepts, patients with advanced non-small-cell lung cancer (NSCLC) still have a very poor prognosis. Therefore, biological markers are urgently needed, which allow the assessment of prognosis, or prediction of the success of therapy or resistance in this disease. Circulating microRNAs (miRs) have potential as biomarkers for the prognosis and prediction of response to therapy in cancer patients. Based on recent evidence that circulating miR-16, miR-29a, miR-144 and miR-150 can be regulated by ionizing radiation, the concentration of these four miRs was assessed in the plasma of NSCLC patients at different time points of radiotherapy by digital droplet PCR (ddPCR). Furthermore, their impact on patients’ prognosis was evaluated. The mean plasma levels of miR-16, miR-29a, miR-144 and miR-150 significantly differed intra- and inter-individually, and during therapy in NSCLC patients, but showed a strong positive correlation. The individual plasma levels of miR-16, miR-29a and miR-144 had prognostic value in NSCLC patients during or at the end of radiotherapy in Cox’s regression models. NSCLC patients with low levels of these three miRs at the end of radiotherapy had the worst prognosis. However, miR-150 plasma levels and treatment-dependent changes were not predictive. In conclusion, circulating miR-16, miR-29a and miR-144, but not miR-150, have a prognostic value in NSCLC patients undergoing radiotherapy. Full article
(This article belongs to the Special Issue Circulating Cell-Free Nucleic Acids and Cancers 2.0)
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17 pages, 1943 KiB  
Article
Phospho-RNA-Seq Highlights Specific Small RNA Profiles in Plasma Extracellular Vesicles
by Maria Solaguren-Beascoa, Ana Gámez-Valero, Georgia Escaramís, Marina Herrero-Lorenzo, Ana M. Ortiz, Carla Minguet, Ricardo Gonzalo, Maria Isabel Bravo, Montserrat Costa and Eulàlia Martí
Int. J. Mol. Sci. 2023, 24(14), 11653; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411653 - 19 Jul 2023
Cited by 1 | Viewed by 1115
Abstract
Small RNAs (sRNAs) are bioactive molecules that can be detected in biofluids, reflecting physiological and pathological states. In plasma, sRNAs are found within extracellular vesicles (EVs) and in extravesicular compartments, offering potential sources of highly sensitive biomarkers. Deep sequencing strategies to profile sRNAs [...] Read more.
Small RNAs (sRNAs) are bioactive molecules that can be detected in biofluids, reflecting physiological and pathological states. In plasma, sRNAs are found within extracellular vesicles (EVs) and in extravesicular compartments, offering potential sources of highly sensitive biomarkers. Deep sequencing strategies to profile sRNAs favor the detection of microRNAs (miRNAs), the best-known class of sRNAs. Phospho-RNA-seq, through the enzymatic treatment of sRNAs with T4 polynucleotide kinase (T4-PNK), has been recently developed to increase the detection of thousands of previously inaccessible RNAs. In this study, we investigated the value of phospho-RNA-seq on both the EVs and extravesicular plasma subfractions. Phospho-RNA-seq increased the proportion of sRNAs used for alignment and highlighted the diversity of the sRNA transcriptome. Unsupervised clustering analysis using sRNA counts matrices correctly classified the EVs and extravesicular samples only in the T4-PNK treated samples, indicating that phospho-RNA-seq stresses the features of sRNAs in each plasma subfraction. Furthermore, T4-PNK treatment emphasized specific miRNA variants differing in the 5′-end (5′-isomiRs) and certain types of tRNA fragments in each plasma fraction. Phospho-RNA-seq increased the number of tissue-specific messenger RNA (mRNA) fragments in the EVs compared with the extravesicular fraction, suggesting that phospho-RNA-seq favors the discovery of tissue-specific sRNAs in EVs. Overall, the present data emphasizes the value of phospho-RNA-seq in uncovering RNA-based biomarkers in EVs. Full article
(This article belongs to the Special Issue Circulating Cell-Free Nucleic Acids and Cancers 2.0)
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13 pages, 2092 KiB  
Article
Utilizing MiSeq Sequencing to Detect Circulating microRNAs in Plasma for Improved Lung Cancer Diagnosis
by Xinyan Geng, Jen-Hui Tsou, Sanford A. Stass and Feng Jiang
Int. J. Mol. Sci. 2023, 24(12), 10277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210277 - 17 Jun 2023
Cited by 1 | Viewed by 1165
Abstract
Non-small cell lung cancer (NSCLC) is a major contributor to cancer-related deaths, but early detection can reduce mortality. NSCLC comprises mainly adenocarcinoma (AC) and squamous cell carcinoma (SCC). Circulating microRNAs (miRNAs) in plasma have emerged as promising biomarkers for NSCLC. However, existing techniques [...] Read more.
Non-small cell lung cancer (NSCLC) is a major contributor to cancer-related deaths, but early detection can reduce mortality. NSCLC comprises mainly adenocarcinoma (AC) and squamous cell carcinoma (SCC). Circulating microRNAs (miRNAs) in plasma have emerged as promising biomarkers for NSCLC. However, existing techniques for analyzing miRNAs have limitations, such as restricted target detection and time-consuming procedures. The MiSeqDx System has been shown to overcome these limitations, making it a promising tool for routine clinical settings. We investigated whether the MiSeqDx could profile cell-free circulating miRNAs in plasma and diagnose NSCLC. We sequenced RNA from the plasma of patients with AC and SCC and from cancer-free smokers using the MiSeqDx to profile and compare miRNA expressions. The MiSeqDx exhibits high speed and accuracy when globally analyzing plasma miRNAs. The entire workflow, encompassing RNA to data analysis, was completed in under three days. We also identified panels of plasma miRNA biomarkers that can diagnose NSCLC with 67% sensitivity and 68% specificity, and detect SCC with 90% sensitivity and 94% specificity, respectively. This study is the first to demonstrate that rapid profiling of plasma miRNAs using the MiSeqDx has the potential to offer a straightforward and effective method for the early detection and classification of NSCLC. Full article
(This article belongs to the Special Issue Circulating Cell-Free Nucleic Acids and Cancers 2.0)
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13 pages, 1527 KiB  
Article
A Case–Control Study by ddPCR of ALU 260/111 and LINE-1 266/97 Copy Number Ratio in Circulating Cell-Free DNA in Plasma Revealed LINE-1 266/97 as a Potential Biomarker for Early Breast Cancer Detection
by Marina Bortul, Fabiola Giudici, Domenico Tierno, Daniele Generali, Serena Scomersi, Gabriele Grassi, Cristina Bottin, Maria Rosa Cappelletti, Fabrizio Zanconati and Bruna Scaggiante
Int. J. Mol. Sci. 2023, 24(10), 8520; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108520 - 10 May 2023
Viewed by 1422
Abstract
Background: In Western countries, breast cancer (BC) is the most common cancer in women. Early detection has a positive impact on survival, quality of life, and public health costs. Mammography screening programs have increased early detection rates, but new approaches to more personalized [...] Read more.
Background: In Western countries, breast cancer (BC) is the most common cancer in women. Early detection has a positive impact on survival, quality of life, and public health costs. Mammography screening programs have increased early detection rates, but new approaches to more personalized surveillance could further improve diagnosis. Circulating cell-free DNA (cfDNA) in blood could provide a potential tool for early diagnosis by analyzing cfDNA quantity, circulating tumor DNA mutations, or cfDNA integrity (cfDI). Methods: Plasma was obtained from the blood of 106 breast cancer patients (cases) and 103 healthy women (controls). Digital droplet PCR was used for the determination of ALU 260/111 bp and LINE-1 266/97 bp copy number ratio and cfDI. cfDNA abundance was calculated using copies of the EEF1A2 gene. The accuracy of biomarker discrimination was analyzed with receiver operating characteristic curve (ROC). Sensitivity analyses were performed to account for age as a potential confounder. Results: Cases had significantly lower ALU 260/111 or LINE-1 266/97 copy number ratios (median; ALU 260/111 = 0.08, LINE-1 266/97 = 0.20), compared with control (median; ALU 260/111 = 0.10, LINE-1 266/97 = 0.28) (p < 0.001). ROC analysis showed that copy number ratio discriminated cases from controls (area under the curve, AUC = 0.69, 95% CI: 0.62–0.76 for ALU and 0.80, 95% CI: 0.73–0.86 for LINE-1). ROC from cfDI confirmed the better diagnostic performance of LINE-1 compared with ALU. Conclusions: Analysis of LINE-1 266/97 copy number ratio or cfDI by ddPCR appears to be a useful noninvasive test that could aid in early BC detection. Further studies in a large cohort are needed to validate the biomarker. Full article
(This article belongs to the Special Issue Circulating Cell-Free Nucleic Acids and Cancers 2.0)
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16 pages, 1525 KiB  
Article
Dynamic Assessment of Tissue and Plasma EGFR-Activating and T790M Mutations with Droplet Digital PCR Assays for Monitoring Response and Resistance in Non-Small Cell Lung Cancers Treated with EGFR-TKIs
by Hsiang-Ling Ho, Fang-Yu Wang, Chi-Lu Chiang, Chun-Ming Tsai, Chao-Hua Chiu and Teh-Ying Chou
Int. J. Mol. Sci. 2022, 23(19), 11353; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911353 - 26 Sep 2022
Cited by 7 | Viewed by 1555
Abstract
Assessing tumor EGFR mutation status is necessary for the proper management of patients with advanced non–small cell lung cancer (NSCLC). We evaluated the impact of dynamic analyses of the plasma and tissue EGFR mutation using ultra-sensitive droplet digital PCR (ddPCR) assays to manage [...] Read more.
Assessing tumor EGFR mutation status is necessary for the proper management of patients with advanced non–small cell lung cancer (NSCLC). We evaluated the impact of dynamic analyses of the plasma and tissue EGFR mutation using ultra-sensitive droplet digital PCR (ddPCR) assays to manage NSCLC patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Paired tumor tissues and plasma samples from 137 EGFR-mutated lung adenocarcinoma patients prior to the first-line EGFR-TKIs treatment (at baseline) and at disease progression were subjected to EGFR mutation analysis using ddPCR, together with the analyses of the clinicopathological characteristics and treatment outcomes. Patients with EGFR-activating mutations detected in baseline plasma were associated with bone metastasis (p = 0.002) and had shorter progression-free survival (12.9 vs. 17.7 months, p = 0.02) and overall survival (24.0 vs. 39.4 months, p = 0.02) compared to those without. Pre-treatment EGFR T790M mutation found in baseline tumor tissues of 28 patients (20.4%; 28/137) was significantly associated with brain metastasis (p = 0.005) and a shorter brain metastasis-free survival (p = 0.001). The presence of EGFR T790M mutations in baseline tumor tissues did not correlate with the emergence of acquired EGFR T790M mutations detected at progression. At disease progression, acquired EGFR T790M mutations were detected in 26.6% (21/79) of the plasma samples and 42.9% (15/35) of the rebiopsy tissues, with a concordance rate of 71.4% (25/35). The dynamic monitoring of tissue and plasma EGFR mutation status at baseline and progression using ddPCR has a clinical impact on the evaluation of EGFR-TKIs treatment efficacy and patient outcomes, as well as the emergence of resistance in NSCLC. Full article
(This article belongs to the Special Issue Circulating Cell-Free Nucleic Acids and Cancers 2.0)
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Review

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20 pages, 1578 KiB  
Review
An Overview of Circulating Cell-Free Nucleic Acids in Diagnosis and Prognosis of Triple-Negative Breast Cancer
by Domenico Tierno, Gabriele Grassi, Fabrizio Zanconati, Marina Bortul and Bruna Scaggiante
Int. J. Mol. Sci. 2023, 24(2), 1799; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021799 - 16 Jan 2023
Cited by 6 | Viewed by 2783
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer due to its molecular heterogeneity and poor clinical outcomes. Analysis of circulating cell-free tumor nucleic acids (ctNAs) can improve our understanding of TNBC and provide efficient and non-invasive clinical biomarkers that may [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer due to its molecular heterogeneity and poor clinical outcomes. Analysis of circulating cell-free tumor nucleic acids (ctNAs) can improve our understanding of TNBC and provide efficient and non-invasive clinical biomarkers that may be representative of tumor heterogeneity. In this review, we summarize the potential of ctNAs to aid TNBC diagnosis and prognosis. For example, tumor fraction of circulating cell-free DNA (TFx) may be useful for molecular prognosis of TNBC: high TFx levels after neoadjuvant chemotherapy have been associated with shorter progression-free survival and relapse-free survival. Mutations and copy number variations of TP53 and PIK3CA/AKT genes in plasma may be important markers of TNBC onset, progression, metastasis, and for clinical follow-up. In contrast, the expression profile of circulating cell-free tumor non-coding RNAs (ctncRNAs) can be predictive of molecular subtypes of breast cancer and thus aid in the identification of TBNC. Finally, dysregulation of some circulating cell-free tumor miRNAs (miR17, miR19a, miR19b, miR25, miR93, miR105, miR199a) may have a predictive value for chemotherapy resistance. In conclusion, a growing number of efforts are highlighting the potential of ctNAs for future clinical applications in the diagnosis, prognosis, and follow-up of TNBC. Full article
(This article belongs to the Special Issue Circulating Cell-Free Nucleic Acids and Cancers 2.0)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Investigation and evaluation of radiation associated miR16, miR29a, miR144 and miR150 in plasma of non-small-cell lung cancer patients

Author: Matthias Bache

Abstract: Despite the success of current therapy concepts, patients with advanced non-small cell lung cancer (NSCLC) still have a very poor prognosis. In this respect, the search for biological markers that can be used to assess the prognosis or predict the success of therapy remains an important area of lung cancer research. Circulating miR have potential as prognostic and predictive biomarkers for cancer patients, but their importance needs to be confirmed in independent studies. In this study, the concentrations of radiation-associated miR-16, miR-29a, miR-144 and miR-150 at different time points of radiotherapy in the plasma of NSCLC patients were determined by digital droplet PCR (ddPCR) and their effects on prognosis and prediction were evaluated.

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