Special Issue "DNA Methylation and Cancer"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 August 2016)

Special Issue Editors

Guest Editor
Prof. Dr. Gerda Egger

Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
Website | E-Mail
Interests: cancer epigenetics; epigenetic biomarkers; DNA methylation; epigenetic therapy; chromatin
Guest Editor
Dr. Melanie R. Hassler

Department of Urology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
Website | E-Mail
Interests: translational epigenetics; DNA methylation in malignant diseases; epigenetic cancer therapy; DNA methylation biomarkers in clinical settings

Special Issue Information

Dear Colleagues,

The field of epigenetics has been the focus of diverse research fields in recent years. It has become clear that epigenetic mechanisms are causally involved in tumorigenesis. Mutations of epigenetic enzymes are frequently found in cancer and especially aberrant patterns of DNA methylation have been extensively explored. Global hypomethylation and local hypermethylation of CpG islands are the hallmarks of the cancer methylome resulting in genomic instability and silencing of underlying genes, respectively. The CpG island methylator phenotype (CIMP) corresponds to certain patient and tumor characteristics, which makes aberrant DNA methylation a promising target for biomarker development. Great hope lies in the field of non-invasive cancer diagnostics using circulating free tumor DNA isolated from liquid biopsies and tumor-specific DNA methylation is a suitable marker for these approaches. Additionally, epigenetic drugs including DNA methyltransferase inhibitors are successfully used in the clinics. Currently a wide range of epigenetic inhibitors are developed and tested in preclinical and clinical studies.

We invite scientists focusing on DNA methylation and cancer to submit their original work or reviews, covering studies on the mechanisms of aberrant DNA methylation in cancer, epigenetic biomarkers or epigenetic therapy. Both translational and basic research papers are welcome.

Prof. Dr. Gerda Egger
Dr. Melanie R. Hassler
Guest Editors

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 papers will be 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. Biomolecules is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 650 CHF (Swiss Francs). 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

  • DNA methylation and cancer
  • Epigenomic profiling in cancer
  • DNA methylation biomarkers
  • Epigenetic therapy
  • DNMT inhibitors

Published Papers (7 papers)

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Research

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Open AccessArticle An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer
Biomolecules 2016, 6(3), 37; doi:10.3390/biom6030037
Received: 21 June 2016 / Revised: 11 August 2016 / Accepted: 12 August 2016 / Published: 2 September 2016
Cited by 2 | PDF Full-text (2245 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination
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Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients. It is also not clear whether a strategy to sensitize chemoresistant patients may exist. We sought to identify cisplatin-resistance patterns in preclinical models of bladder cancer, and test whether treatment with the epigenetic modifier decitabine is able to sensitize cisplatin-resistant bladder cancer cell lines. Using a screening approach in cisplatin-resistant bladder cancer cell lines, we identified dysregulated genes by RNA sequencing (RNAseq) and DNA methylation assays. DNA methylation analysis of tumors from 18 patients receiving cisplatin-based chemotherapy was used to confirm in vitro results. Cisplatin-resistant bladder cancer cells were treated with decitabine to investigate epigenetic sensitization of resistant cell lines. Our results show that HOXA9 promoter methylation status is associated with response to cisplatin-based chemotherapy in bladder cancer cell lines and in metastatic bladder cancer. Bladder cancer cells resistant to cisplatin chemotherapy can be sensitized to cisplatin by the DNA methylation inhibitor decitabine. Our data suggest that HOXA9 promoter methylation could serve as potential predictive biomarker and decitabine might sensitize resistant tumors in patients receiving cisplatin-based chemotherapy. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Review

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Open AccessReview The Process and Regulatory Components of Inflammation in Brain Oncogenesis
Biomolecules 2017, 7(2), 34; doi:10.3390/biom7020034
Received: 31 January 2017 / Revised: 9 March 2017 / Accepted: 22 March 2017 / Published: 27 March 2017
Cited by 2 | PDF Full-text (3929 KB) | HTML Full-text | XML Full-text
Abstract
Central nervous system tumors comprising the primary cancers and brain metastases remain the most lethal neoplasms and challenging to treat. Substantial evidence points to a paramount role for inflammation in the pathology leading to gliomagenesis, malignant progression and tumor aggressiveness in the central
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Central nervous system tumors comprising the primary cancers and brain metastases remain the most lethal neoplasms and challenging to treat. Substantial evidence points to a paramount role for inflammation in the pathology leading to gliomagenesis, malignant progression and tumor aggressiveness in the central nervous system (CNS) microenvironment. This review summarizes the salient contributions of oxidative stress, interleukins, tumor necrosis factor-α (TNF-α), cyclooxygenases, and transcription factors such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and the associated cross-talks to the inflammatory signaling in CNS cancers. The roles of reactive astrocytes, tumor associated microglia and macrophages, metabolic alterations, microsatellite instability, O6-methylguanine DNA methyltransferase (MGMT) DNA repair and epigenetic alterations mediated by the isocitrate dehydrogenase 1 (IDH1) mutations have been discussed. The inflammatory pathways with relevance to the brain cancer treatments have been highlighted. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Open AccessReview The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer
Biomolecules 2017, 7(1), 15; doi:10.3390/biom7010015
Received: 30 November 2016 / Revised: 23 January 2017 / Accepted: 6 February 2017 / Published: 14 February 2017
Cited by 1 | PDF Full-text (1020 KB) | HTML Full-text | XML Full-text
Abstract
The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental
[...] Read more.
The process of DNA CpG methylation has been extensively investigated for over 50 years and revealed associations between changing methylation status of CpG islands and gene expression. As a result, DNA CpG methylation is implicated in the control of gene expression in developmental and homeostasis processes, as well as being a cancer-driver mechanism. The development of genome-wide technologies and sophisticated statistical analytical approaches has ushered in an era of widespread analyses, for example in the cancer arena, of the relationships between altered DNA CpG methylation, gene expression, and tumor status. The remarkable increase in the volume of such genomic data, for example, through investigators from the Cancer Genome Atlas (TCGA), has allowed dissection of the relationships between DNA CpG methylation density and distribution, gene expression, and tumor outcome. In this manner, it is now possible to test that the genome-wide correlations are measurable between changes in DNA CpG methylation and gene expression. Perhaps surprisingly is that these associations can only be detected for hundreds, but not thousands, of genes, and the direction of the correlations are both positive and negative. This, perhaps, suggests that CpG methylation events in cancer systems can act as disease drivers but the effects are possibly more restricted than suspected. Additionally, the positive and negative correlations suggest direct and indirect events and an incomplete understanding. Within the prostate cancer TCGA cohort, we examined the relationships between expression of genes that control DNA methylation, known targets of DNA methylation and tumor status. This revealed that genes that control the synthesis of S-adenosyl-l-methionine (SAM) associate with altered expression of DNA methylation targets in a subset of aggressive tumors. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Open AccessReview DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge
Biomolecules 2017, 7(1), 3; doi:10.3390/biom7010003
Received: 15 November 2016 / Revised: 8 December 2016 / Accepted: 12 December 2016 / Published: 5 January 2017
Cited by 4 | PDF Full-text (1284 KB) | HTML Full-text | XML Full-text
Abstract
Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each
[...] Read more.
Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Open AccessReview Epigenetic Impact on EBV Associated B-Cell Lymphomagenesis
Biomolecules 2016, 6(4), 46; doi:10.3390/biom6040046
Received: 20 September 2016 / Revised: 2 November 2016 / Accepted: 7 November 2016 / Published: 24 November 2016
PDF Full-text (1301 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetic modifications leading to either transcriptional repression or activation, play an indispensable role in the development of human cancers. Epidemiological study revealed that approximately 20% of all human cancers are associated with tumor viruses. Epstein-Barr virus (EBV), the first human tumor virus, demonstrates
[...] Read more.
Epigenetic modifications leading to either transcriptional repression or activation, play an indispensable role in the development of human cancers. Epidemiological study revealed that approximately 20% of all human cancers are associated with tumor viruses. Epstein-Barr virus (EBV), the first human tumor virus, demonstrates frequent epigenetic alterations on both viral and host genomes in associated cancers—both of epithelial and lymphoid origin. The cell type-dependent different EBV latent gene expression patterns appear to be determined by the cellular epigenetic machinery and similarly viral oncoproteins recruit epigenetic regulators in order to deregulate the cellular gene expression profile resulting in several human cancers. This review elucidates the epigenetic consequences of EBV–host interactions during development of multiple EBV-induced B-cell lymphomas, which may lead to the discovery of novel therapeutic interventions against EBV-associated B-cell lymphomas by alteration of reversible patho-epigenetic markings. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Open AccessReview The Emergence of Pan-Cancer CIMP and Its Elusive Interpretation
Biomolecules 2016, 6(4), 45; doi:10.3390/biom6040045
Received: 30 August 2016 / Revised: 8 November 2016 / Accepted: 11 November 2016 / Published: 22 November 2016
Cited by 3 | PDF Full-text (1098 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetic dysregulation is recognized as a hallmark of cancer. In the last 16 years, a CpG island methylator phenotype (CIMP) has been documented in tumors originating from different tissues. However, a looming question in the field is whether or not CIMP is a
[...] Read more.
Epigenetic dysregulation is recognized as a hallmark of cancer. In the last 16 years, a CpG island methylator phenotype (CIMP) has been documented in tumors originating from different tissues. However, a looming question in the field is whether or not CIMP is a pan-cancer phenomenon or a tissue-specific event. Here, we give a synopsis of the history of CIMP and describe the pattern of DNA methylation that defines the CIMP phenotype in different cancer types. We highlight new conceptual approaches of classifying tumors based on CIMP in a cancer type-agnostic way that reveal the presence of distinct CIMP tumors in a multitude of The Cancer Genome Atlas (TCGA) datasets, suggesting that this phenotype may transcend tissue-type specificity. Lastly, we show evidence supporting the clinical relevance of CIMP-positive tumors and suggest that a common CIMP etiology may define new mechanistic targets in cancer treatment. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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Open AccessReview Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents
Biomolecules 2016, 6(3), 32; doi:10.3390/biom6030032
Received: 29 April 2016 / Revised: 9 June 2016 / Accepted: 27 June 2016 / Published: 4 July 2016
PDF Full-text (1175 KB) | HTML Full-text | XML Full-text
Abstract
First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved,
[...] Read more.
First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity. Full article
(This article belongs to the Special Issue DNA Methylation and Cancer)
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