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Circulating DNA and Epigenetic Alterations as Biomarkers in Oncology

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 27581

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Special Issue Editors

Prof. Dr. Aristidis M. Tsatsakis

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Guest Editor

Laboratory of Toxicology, Medical School, University of Crete, Voutes, 700 13 Heraklion, Crete, Greece
Interests: biomonitoring and risk assessments of xenobiotics; biomarkers of exposure and of effects for various chemicals; pesticide toxicology; epidemiology and hygiene
Special Issues, Collections and Topics in MDPI journals

Dr. Taxiarchis Konstantinos Nikolouzakis

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Assistant Editor

Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion, Greece
Interests: cancer biology; surgery; anatomy; colorectal cancer; micronuclei; telomere length

Dr. Sotirios Doukas

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Assistant Editor

1. Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
2. Department of Internal Medicine, Saint Peter's University Hospital, New Brunswick, NJ 08901, USA
Interests: medicine; oncology; gastroenterology; cancer research; biomarkers; epigenetics

Dr. Luca Falzone

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Assistant Editor

Department of Biomedical and Biotechnological Sciences, Universita degli Studi di Catania, Catania, Italy
Interests: cancer; epigenetics; biomarkers; microRNAs; DNA methylation; occupational carcinogens
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It has been widely demonstrated that the development of tumors is driven by several alterations affecting gene structure and function. Among these alterations, the most studied have been DNA mutations affecting key genes involved in the regulation of cell cycle and cell proliferation. Recently, it was shown that epigenetic alterations, such as DNA methylation, histone modifications, and deregulation of noncoding RNAs (ncRNA), are also involved in neoplastic transformation by inducing the overexpression of oncogenes and the silencing of tumor suppressor genes. It has also been shown that tumor cells, as a consequence of necrotic and apoptotic processes, release in the bloodstream and tumor microenvironment ncRNA and fragments of tumor DNA, the so-called circulating tumor DNA (ctDNA), reflecting the tumor mutational burden. As early events of neoplastic transformation, the identification of ctDNA and epigenetic alterations would allow the early diagnosis of tumor, thus representing ideal tumor biomarkers. Furthermore, several patterns of genetic and epigenetic alterations have been associated to specific clinical–pathological features of tumors; therefore, both DNA mutations and epigenetic alterations can also be used as prognostic biomarkers and for the monitoring of the therapeutic response.

On these bases, a growing body of evidence demonstrated that the use of liquid biopsy could represent an effective strategy to improve both diagnostic and prognostic procedures for the management of cancer patients. In particular, the identification of circulating tumor DNA and epigenetic biomarkers through the analysis of liquid biopsy samples and the use of high-sensitive molecular technologies has proven to be effective in identifying the presence of several tumors early, thus improving the quality of life and survival of cancer patients.

On these bases, the aim of this Special Issue will be to point out the main findings regarding the identification of ctDNA and epigenetic alterations and their potential role as tumor biomarkers, as well as the use of liquid biopsy and high-throughput technologies as new diagnostic and prognostic strategies in oncology.

Potential topics will include but are not limited to:

Circulating tumor DNA as diagnostic and prognostic biomarkers in oncology;
Epigenetic alterations in oncology;
DNA methylation hotspots as an early marker of neoplastic transformation;
Application of liquid biopsy in oncology;
miRNA and epigenetic alterations as early events of neoplastic transformation after environmental and occupational exposure to pollutants;
Circulating biomarkers for therapeutic monitoring;
Liquid biopsy and circulating biomarkers for personalized cancer therapy;
Epigenetic biomarkers for prediction of anticancer treatment response, drug resistance, and drug toxicity.

Dr. Aristidis M. Tsatsakis
Guest Editors

Manuscript Submission Information

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Keywords

cancer
circulating DNA
epigenetics
liquid biopsy
microRNAs
methylation
diagnosis
prognosis
drug resistance
toxicity

Published Papers (4 papers)

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Research

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12 pages, 1296 KiB

Open AccessArticle

CpG-Islands as Markers for Liquid Biopsies of Cancer Patients

by Maximilian Sprang, Claudia Paret and Joerg Faber

Cells 2020, 9(8), 1820; https://doi.org/10.3390/cells9081820 - 01 Aug 2020

Cited by 12 | Viewed by 2965

Abstract

The analysis of tumours using biomarkers in blood is transforming cancer diagnosis and therapy. Cancers are characterised by evolving genetic alterations, making it difficult to develop reliable and broadly applicable DNA-based biomarkers for liquid biopsy. In contrast to the variability in gene mutations, the methylation pattern remains generally constant during carcinogenesis. Thus, methylation more than mutation analysis may be exploited to recognise tumour features in the blood of patients. In this work, we investigated the possibility of using global CpG (CpG means a CG motif in the context of methylation. The p represents the phosphate. This is used to distinguish CG sites meant for methylation from other CG motifs or from mentions of CG content) island methylation profiles as a basis for the prediction of cancer state of patients utilising liquid biopsy samples. We retrieved existing GEO methylation datasets on hepatocellular carcinoma (HCC) and cell-free DNA (cfDNA) from HCC patients and healthy donors, as well as healthy whole blood and purified peripheral blood mononuclear cell (PBMC) samples, and used a random forest classifier as a predictor. Additionally, we tested three different feature selection techniques in combination. When using cfDNA samples together with solid tumour samples and healthy blood samples of different origin, we could achieve an average accuracy of 0.98 in a 10-fold cross-validation. In this setting, all the feature selection methods we tested in this work showed promising results. We could also show that it is possible to use solid tumour samples and purified PBMCs as a training set and correctly predict a cfDNA sample as cancerous or healthy. In contrast to the complete set of samples, the feature selections led to varying results of the respective random forests. ANOVA feature selection worked well with this training set, and the selected features allowed the random forest to predict all cfDNA samples correctly. Feature selection based on mutual information could also lead to better than random results, but LASSO feature selection would not lead to a confident prediction. Our results show the relevance of CpG islands as tumour markers in blood. Full article

(This article belongs to the Special Issue Circulating DNA and Epigenetic Alterations as Biomarkers in Oncology)

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22 pages, 5547 KiB

Open AccessArticle

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

by Sotirios G. Doukas, Dimitra P. Vageli, George Lazopoulos, Demetrios A. Spandidos, Clarence T. Sasaki and Aristidis Tsatsakis

Cells 2020, 9(4), 1031; https://doi.org/10.3390/cells9041031 - 21 Apr 2020

Cited by 33 | Viewed by 4217

Abstract

Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 μM) or high (2 μM) dose of NNK induced significant upregulation of “oncomirs” miR-21 and miR-155 and downregulation of “tumor suppressor” miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers. Full article

(This article belongs to the Special Issue Circulating DNA and Epigenetic Alterations as Biomarkers in Oncology)

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Review

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22 pages, 1590 KiB

Open AccessReview

Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development

by David R. Wallace, Yasmeen M. Taalab, Sarah Heinze, Blanka Tariba Lovaković, Alica Pizent, Elisavet Renieri, Aristidis Tsatsakis, Ammad Ahmad Farooqi, Dragana Javorac, Milena Andjelkovic, Zorica Bulat, Biljana Antonijević and Aleksandra Buha Djordjevic

Cells 2020, 9(4), 901; https://doi.org/10.3390/cells9040901 - 07 Apr 2020

Cited by 92 | Viewed by 7410

Abstract

Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)—short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain—a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs). Full article

(This article belongs to the Special Issue Circulating DNA and Epigenetic Alterations as Biomarkers in Oncology)

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32 pages, 2039 KiB

Open AccessEditor’s ChoiceReview

DNA Methylation-Based Testing in Liquid Biopsies as Detection and Prognostic Biomarkers for the Four Major Cancer Types

by Vera Constâncio, Sandra P. Nunes, Rui Henrique and Carmen Jerónimo

Cells 2020, 9(3), 624; https://doi.org/10.3390/cells9030624 - 05 Mar 2020

Cited by 99 | Viewed by 12158

Abstract

Lung, breast, colorectal, and prostate cancers are the most incident worldwide. Optimal population-based cancer screening methods remain an unmet need, since cancer detection at early stages increases the prospects of successful and curative treatment, leading to a lower incidence of recurrences. Moreover, the current parameters for cancer patients’ stratification have been associated with divergent outcomes. Therefore, new biomarkers that could aid in cancer detection and prognosis, preferably detected by minimally invasive methods are of major importance. Aberrant DNA methylation is an early event in cancer development and may be detected in circulating cell-free DNA (ccfDNA), constituting a valuable cancer biomarker. Furthermore, DNA methylation is a stable alteration that can be easily and rapidly quantified by methylation-specific PCR methods. Thus, the main goal of this review is to provide an overview of the most important studies that report methylation biomarkers for the detection and prognosis of the four major cancers after a critical analysis of the available literature. DNA methylation-based biomarkers show promise for cancer detection and management, with some studies describing a “PanCancer” detection approach for the simultaneous detection of several cancer types. Nonetheless, DNA methylation biomarkers still lack large-scale validation, precluding implementation in clinical practice. Full article

(This article belongs to the Special Issue Circulating DNA and Epigenetic Alterations as Biomarkers in Oncology)

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