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7.4
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Cancers
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DNA Methylation in Cancer
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DNA Methylation in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (15 July 2022) | Viewed by 19066

Special Issue Editors

Dr. Patrizia Zavattari

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Cagliari, 09042 Cagliari, Italy
Interests: DNA methylation alterations; somatic mutations and epimutations in solid and blood cancers; genomics; epigenomics; genetics of complex traits; trace elements and multifactorial diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Eleonora Loi

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Cagliari, 09042 Cagliari, Italy
Interests: DNA methylation alterations; bioinformatic analysis of genomic and epigenomic data; epigenome editing; 2D and 3D cellular models; epigenomics
Special Issues, Collections and Topics in MDPI journals
Dr. Sergio Alonso

E-Mail Website
Guest Editor
Program of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain
Interests: cancer epigenomics; cancer genomics; gastrointestinal cancer; DNA methylation

Special Issue Information

Dear Colleagues,

DNA methylation alterations underlie the carcinogenic process from its earliest stages. This is characterized by global losses of DNA methylation coupled with localized ectopic gains of DNA methylation at CpG islands, which are frequently associated with gene expression changes. A homeostatic balance between heterochromatin and euchromatin is essential to genomic stability. This Special Issue will give an overview of the various aspects that these epigenetic changes represent in cancer. Topics of interest will include but are not limited to the following: potential biomarkers for early detection and important prognostic and predictive markers to improve therapeutic interventions; the detection of these biomarkers through less invasive or noninvasive procedures; new therapeutic approaches based on epigenetic reprograming; improved knowledge of the cellular processes affected by such early changes in the context of future functional studies.

Prof. Dr. Patrizia Zavattari 
Dr. Eleonora Loi
Dr. Sergio Alonso
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 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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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 alterations in cancer
  • cancer DNA methylation-based biomarkers
  • epigenome editing
  • ctDNA
  • cfDNA
  • noninvasive cancer biomarker detection
  • DNA methylation and gene expression
  • CpG islands alteration in cancer
  • DNMT
  • TET

Published Papers (6 papers)

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Research

15 pages, 3503 KiB  
Article
Preliminary Study on the Sequencing of Whole Genomic Methylation and Transcriptome-Related Genes in Thyroid Carcinoma
by Muhammad Asad Iqbal, Mingyang Li, Jiang Lin, Guoliang Zhang, Miao Chen, Nida Fatima Moazzam and Wei Qian
Cancers 2022, 14(5), 1163; https://doi.org/10.3390/cancers14051163 - 24 Feb 2022
Cited by 6 | Viewed by 2743
Abstract
Thyroid carcinoma is the most prevalent endocrine cancer globally and the primary cause of cancer-related mortality. Epigenetic modifications are progressively being linked to metastasis. This study aimed to examine whole-genome DNA methylation patterns and the gene expression profiles in thyroid cancer tissue samples [...] Read more.
Thyroid carcinoma is the most prevalent endocrine cancer globally and the primary cause of cancer-related mortality. Epigenetic modifications are progressively being linked to metastasis. This study aimed to examine whole-genome DNA methylation patterns and the gene expression profiles in thyroid cancer tissue samples using a MethylationEPIC BeadChip (850K), RNA sequencing, and a targeted bisulfite sequencing assay. The results of the Illumina Infinium human methylation kit (850K) analyses identified differentially methylated CpG locations (DMPs) and differentially methylated CpG regions (DMRs) encompassing nearly the entire genome with high resolution and depth. Gene ontology and KEGG pathway analyses revealed that the genes associated with DMRs belonged to various domain-specific ontologies, including cell adhesion, molecule binding, and proliferation. The RNA-Seq study found 1627 differentially expressed genes, 1174 of which that were up-regulated and 453 of which that were down-regulated. The targeted bisulfite sequencing assay revealed that CHST2, DPP4, DUSP6, ITGA2, SLC1A5, TIAM1, TNIK, and ABTB2 methylation levels were dramatically lowered in thyroid cancer patients when compared to the controls, but GALNTL6, HTR7, SPOCD1, and GRM5 methylation levels were significantly raised. Our study revealed that the whole-genome DNA methylation patterns and gene expression profiles in thyroid cancer shed new light on the tumorigenesis of thyroid cancer. Full article
(This article belongs to the Special Issue DNA Methylation in Cancer)
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15 pages, 1530 KiB  
Article
Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma
by Benjamin Emil Stubbe, Stine Dam Henriksen, Poul Henning Madsen, Anders Christian Larsen, Henrik Bygum Krarup, Inge Søkilde Pedersen, Martin Nygård Johansen and Ole Thorlacius-Ussing
Cancers 2021, 13(22), 5717; https://doi.org/10.3390/cancers13225717 - 15 Nov 2021
Cited by 8 | Viewed by 3028
Abstract
No reliable predictive blood-based biomarkers are available for determining survival from pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examines promoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derived cell-free DNA as an independent prognostic marker for survival and Gemcitabine [...] Read more.
No reliable predictive blood-based biomarkers are available for determining survival from pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examines promoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derived cell-free DNA as an independent prognostic marker for survival and Gemcitabine effectiveness in patients with stage IV PDAC. We conducted methylation-specific polymerase chain reaction analysis of the promoter region of the SFRP1 gene, based on bisulfite treatment. Survival was analyzed with Kaplan–Meier curves, log-rank test, and Cox regression. The discovery cohort included 40 patients, 25 receiving Gem. Gem-treated patients with phSFRP1 had a shorter median overall survival (mOS) (4.4 months) than unmethylated patients (11.6 months). Adjusted Cox-regression yielded a hazard rate (HR) of 3.48 (1.39–8.70). The validation cohort included 58 Gem-treated patients. Patients with phSFRP1 had a shorter mOS (3.2 months) than unmethylated patients (6.3 months). Adjusted Cox regression yielded an HR of 3.53 (1.85–6.74). In both cohorts, phSFRP1 was associated with poorer survival in Gem-treated patients. This may indicate that tumors with phSFRP1 are more aggressive and less sensitive to Gem treatment. This knowledge may facilitate tailored treatment of patients with stage IV PDAC. Further studies are planned to examine phSFRP1 in more intensive chemotherapy regimens. Full article
(This article belongs to the Special Issue DNA Methylation in Cancer)
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18 pages, 2573 KiB  
Article
Cancer Detection and Classification by CpG Island Hypermethylation Signatures in Plasma Cell-Free DNA
by Jinyong Huang, Alex C. Soupir, Brian D. Schlick, Mingxiang Teng, Ibrahim H. Sahin, Jennifer B. Permuth, Erin M. Siegel, Brandon J. Manley, Bruna Pellini and Liang Wang
Cancers 2021, 13(22), 5611; https://doi.org/10.3390/cancers13225611 - 09 Nov 2021
Cited by 8 | Viewed by 3770
Abstract
Cell-free DNA (cfDNA) methylation has emerged as a promising biomarker for early cancer detection, tumor type classification, and treatment response monitoring. Enrichment-based cfDNA methylation profiling methods such as cfMeDIP-seq have shown high accuracy in the classification of multiple cancer types. We have previously [...] Read more.
Cell-free DNA (cfDNA) methylation has emerged as a promising biomarker for early cancer detection, tumor type classification, and treatment response monitoring. Enrichment-based cfDNA methylation profiling methods such as cfMeDIP-seq have shown high accuracy in the classification of multiple cancer types. We have previously optimized another enrichment-based approach for ultra-low input cfDNA methylome profiling, termed cfMBD-seq. We reported that cfMBD-seq outperforms cfMeDIP-seq in the enrichment of high-CpG-density regions, such as CpG islands. However, the clinical feasibility of cfMBD-seq is unknown. In this study, we applied cfMBD-seq to profiling the cfDNA methylome using plasma samples from cancer patients and non-cancer controls. We identified 1759, 1783, and 1548 differentially hypermethylated CpG islands (DMCGIs) in lung, colorectal, and pancreatic cancer patients, respectively. Interestingly, the vast majority of DMCGIs were overlapped with aberrant methylation changes in corresponding tumor tissues, indicating that DMCGIs detected by cfMBD-seq were mainly driven by tumor-specific DNA methylation patterns. From the overlapping DMCGIs, we carried out machine learning analyses and identified a set of discriminating methylation signatures that had robust performance in cancer detection and classification. Overall, our study demonstrates that cfMBD-seq is a powerful tool for sensitive detection of tumor-derived epigenomic signals in cfDNA. Full article
(This article belongs to the Special Issue DNA Methylation in Cancer)
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22 pages, 2726 KiB  
Article
Somatic Hypomethylation of Pericentromeric SST1 Repeats and Tetraploidization in Human Colorectal Cancer Cells
by Beatriz González, Maria Navarro-Jiménez, María José Alonso-De Gennaro, Sanne Marcia Jansen, Isabel Granada, Manuel Perucho and Sergio Alonso
Cancers 2021, 13(21), 5353; https://doi.org/10.3390/cancers13215353 - 26 Oct 2021
Cited by 4 | Viewed by 2306
Abstract
Somatic DNA hypomethylation and aneuploidy are hallmarks of cancer, and there is evidence for a causal relationship between them in knockout mice but not in human cancer. The non-mobile pericentromeric repetitive elements SST1 are hypomethylated in about 17% of human colorectal cancers (CRC) [...] Read more.
Somatic DNA hypomethylation and aneuploidy are hallmarks of cancer, and there is evidence for a causal relationship between them in knockout mice but not in human cancer. The non-mobile pericentromeric repetitive elements SST1 are hypomethylated in about 17% of human colorectal cancers (CRC) with some 5–7% exhibiting strong age-independent demethylation. We studied the frequency of genome doubling, a common event in solid tumors linked to aneuploidy, in randomly selected single cell clones of near-diploid LS174T human CRC cells differing in their level of SST1 demethylation. Near-diploid LS174T cells underwent frequent genome-doubling events generating near-tetraploid clones with lower levels of SST1 methylation. In primary CRC, strong SST1 hypomethylation was significantly associated with global genomic hypomethylation and mutations in TP53. This work uncovers the association of the naturally occurring demethylation of the SST1 pericentromeric repeat with the onset of spontaneous tetraploidization in human CRC cells in culture and with TP53 mutations in primary CRCs. Altogether, our findings provide further support for an oncogenic pathway linking somatic hypomethylation and genetic copy number alterations in a subset of human CRC. Full article
(This article belongs to the Special Issue DNA Methylation in Cancer)
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19 pages, 8157 KiB  
Article
Upper Aerodigestive Tract Squamous Cell Carcinomas Show Distinct Overall DNA Methylation Profiles and Different Molecular Mechanisms behind WNT Signaling Disruption
by Sheila Coelho Soares-Lima, Hisham Mehanna, Diego Camuzi, Paulo Thiago de Souza-Santos, Tatiana de Almeida Simão, Pedro Nicolau-Neto, Monique de Souza Almeida Lopes, Cyrille Cuenin, Fazlur Rahman Talukdar, Nikolaos Batis, Izabella Costa, Fernando Dias, Davide Degli Esposti, Mariana Boroni, Zdenko Herceg and Luis Felipe Ribeiro Pinto
Cancers 2021, 13(12), 3014; https://doi.org/10.3390/cancers13123014 - 16 Jun 2021
Cited by 8 | Viewed by 2731
Abstract
Upper aerodigestive tract (UADT) tumors present different biological behavior and prognosis, suggesting specific molecular mechanisms underlying their development. However, they are rarely considered as single entities (particularly head and neck subsites) and share the most common genetic alterations. Therefore, there is a need [...] Read more.
Upper aerodigestive tract (UADT) tumors present different biological behavior and prognosis, suggesting specific molecular mechanisms underlying their development. However, they are rarely considered as single entities (particularly head and neck subsites) and share the most common genetic alterations. Therefore, there is a need for a better understanding of the global DNA methylation differences among UADT tumors. We performed a genome-wide DNA methylation analysis of esophageal (ESCC), laryngeal (LSCC), oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas, and their non-tumor counterparts. The unsupervised analysis showed that non-tumor tissues present markedly distinct DNA methylation profiles, while tumors are highly heterogeneous. Hypomethylation was more frequent in LSCC and OPSCC, while ESCC and OSCC presented mostly hypermethylation, with the latter showing a CpG island overrepresentation. Differentially methylated regions affected genes in 127 signaling pathways, with only 3.1% of these being common among different tumor subsites, but with different genes affected. The WNT signaling pathway, known to be dysregulated in different epithelial tumors, is a frequent hit for DNA methylation and gene expression alterations in ESCC and OPSCC, but mostly for genetic alterations in LSCC and OSCC. UADT tumor subsites present differences in genome-wide methylation regarding their profile, intensity, genomic regions and signaling pathways affected. Full article
(This article belongs to the Special Issue DNA Methylation in Cancer)
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17 pages, 2416 KiB  
Article
Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions
by Antonio Gómez, Miguel L. Pato, Luis Bujanda, Núria Sala, Osmel Companioni, Ángel Cosme, Martina Tufano, David J. Hanly, Nadia García, José Miguel Sanz-Anquela, Javier P. Gisbert, Consuelo López, José Ignacio Elizalde, Miriam Cuatrecasas, Victoria Andreu, María José Paules, María Dolores Martín-Arranz, Luis Ortega, Elvira Poves, Jesús Barrio, María Ángeles Torres, Guillermo Muñoz, Ángel Ferrández, María José Ramírez-Lázaro, Sergio Lario, Carlos A González, Manel Esteller and María Berdascoadd Show full author list remove Hide full author list
Cancers 2021, 13(11), 2760; https://doi.org/10.3390/cancers13112760 - 02 Jun 2021
Cited by 6 | Viewed by 3235
Abstract
To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery [...] Read more.
To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature. Full article
(This article belongs to the Special Issue DNA Methylation in Cancer)
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