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Cancers
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Cancer Epigenetic Biomarkers
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Cancer Epigenetic Biomarkers

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

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 27418

Special Issue Editor

Prof. Dr. Fabio Coppedè

E-Mail Website
Guest Editor
Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
Interests: cancer genetics; cancer epigenetics; DNA methylation; cancer biomarkers; pharmacoepigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer represents one of the most threatening human diseases, with millions of diagnosed novel cases and deaths occurring worldwide every year. The global aging of the population and the increased exposure to environmental carcinogens, coupled with the adoption of lifestyle behaviors such as smoking, poor diets, and scarce physical activity, account for the majority of cancers in both developed and less-developed countries.

It is also well ascertained that genetic, epigenetic, and cytogenetic modifications occur within cancer cells and tissue, many of which are driven by environmental exposures and are responsible for the acquisition of the malignant phenotype. Particularly, it is now clear that hundreds of genes change their expression in the multistep process of carcinogenesis as a consequence of epigenetic events, including promoter hypermethylation, histone-tail modifications, chromatin remodeling, or interference mechanisms mediated by non-coding RNA molecules.

Some of these epigenetic marks are gathering increasing interest in the clinical setting as valid diagnostic or prognostic biomarkers of the disease, as well as response predictors to therapy. This Special Issue will focus on the most recent advances in cancer epigenetics, as well as on the discovery and utility of cancer epigenetic biomarkers.

Prof. Dr. Fabio Coppedè
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 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

  • cancer
  • biomarker
  • epigenetics
  • DNA methylation
  • miRNA
  • diagnostic biomarkers
  • pharmacoepigenetics
  • epigenetic drugs

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Published Papers (10 papers)

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Editorial

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3 pages, 200 KiB  
Editorial
Cancer Epigenetic Biomarkers
by Fabio Coppedè
Cancers 2023, 15(22), 5365; https://doi.org/10.3390/cancers15225365 - 10 Nov 2023
Viewed by 1047
Abstract
This series of nine articles (six original articles, three reviews) is presented by international experts in cancer epigenetics [...] Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)

Research

Jump to: Editorial, Review

18 pages, 1795 KiB  
Article
Examination of the Functional Relationship between PD-L1 DNA Methylation and mRNA Expression in Non-Small-Cell Lung Cancer
by Trine V. Larsen, Nina Dybdal, Tina F. Daugaard, Johanne Lade-Keller, Lin Lin, Boe S. Sorensen and Anders L. Nielsen
Cancers 2023, 15(6), 1909; https://doi.org/10.3390/cancers15061909 - 22 Mar 2023
Cited by 6 | Viewed by 2888
Abstract
Immunotherapy targeting the interaction between programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is a treatment option for patients with non-small-cell lung cancer (NSCLC). The expression of PD-L1 by the NSCLC cells determines treatment effectiveness, but the relationship between PD-L1 [...] Read more.
Immunotherapy targeting the interaction between programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is a treatment option for patients with non-small-cell lung cancer (NSCLC). The expression of PD-L1 by the NSCLC cells determines treatment effectiveness, but the relationship between PD-L1 DNA methylation and expression has not been clearly described. We investigated PD-L1 DNA methylation, mRNA expression, and protein expression in NSCLC cell lines and tumor biopsies. We used clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) to modify PD-L1 genetic contexts and endonuclease deficient Cas9 (dCas9) fusions with ten-eleven translocation methylcytosine dioxygenase 1 (TET1) and DNA (cytosine-5)-methyltransferase 3A (DNMT3A) to manipulate PD-L1 DNA methylation. In NSCLC cell lines, we identified specific PD-L1 CpG sites with methylation levels inversely correlated with PD-L1 mRNA expression. However, inducing PD-L1 mRNA expression with interferon-γ did not decrease the methylation level for these CpG sites, and using CRISPR-Cas9, we found that the CpG sites did not directly confer a negative regulation. dCas9-TET1 and dCas9-DNMT3A could induce PD-L1 hypo- and hyper-methylation, respectively, with the latter conferring a decrease in expression showing the functional impact of methylation. In NSCLC biopsies, the inverse correlation between the methylation and expression of PD-L1 was weak. We conclude that there is a regulatory link between PD-L1 DNA methylation and expression. However, since these measures are weakly associated, this study highlights the need for further research before PD-L1 DNA methylation can be implemented as a biomarker and drug target for measures to improve the effectiveness of PD-1/PD-L1 immunotherapy in NSCLC. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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11 pages, 862 KiB  
Article
Methylated Cell-Free DNA Sequencing (MeD-seq) of LpnPI Digested Fragments to Identify Early Progression in Metastatic Renal Cell Carcinoma Patients on Watchful Waiting
by Manouk K. Bos, Sarah R. Verhoeff, Sjoukje F. Oosting, Willemien C. Menke-van der Houven van Oordt, Ruben G. Boers, Joachim B. Boers, Joost Gribnau, John W. M. Martens, Stefan Sleijfer, Carla M. L. van Herpen and Saskia M. Wilting
Cancers 2023, 15(5), 1374; https://doi.org/10.3390/cancers15051374 - 21 Feb 2023
Cited by 1 | Viewed by 1843
Abstract
According to the current guidelines, watchful waiting (WW) is a feasible option for patients with good or intermediate prognosis renal-cell carcinoma (RCC). However, some patients rapidly progress during WW, requiring the initiation of treatment. Here, we explore whether we can identify those patients [...] Read more.
According to the current guidelines, watchful waiting (WW) is a feasible option for patients with good or intermediate prognosis renal-cell carcinoma (RCC). However, some patients rapidly progress during WW, requiring the initiation of treatment. Here, we explore whether we can identify those patients using circulating cell-free DNA (cfDNA) methylation. We first defined a panel of RCC-specific circulating methylation markers by intersecting differentially methylated regions from a publicly available dataset with known RCC methylation markers from the literature. The resulting RCC-specific methylation marker panel of 22 markers was subsequently evaluated for an association with rapid progression by methylated DNA sequencing (MeD-seq) in serum from 10 HBDs and 34 RCC patients with a good or intermediate prognosis starting WW in the IMPACT-RCC study. Patients with an elevated RCC-specific methylation score compared to HBDs had a shorter progression-free survival (PFS, p = 0.018), but not a shorter WW-time (p = 0.15). Cox proportional hazards regression showed that only the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria were significantly associated with WW time (HR 2.01, p = 0.01), whereas only our RCC-specific methylation score (HR 4.45, p = 0.02) was significantly associated with PFS. The results of this study suggest that cfDNA methylation is predictive of PFS but not WW. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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17 pages, 3914 KiB  
Article
Integrative Clinical and DNA Methylation Analyses in a Population-Based Cohort Identifies CDH17 and LRP2 as Risk Recurrence Factors in Stage II Colon Cancer
by Benjamin Tournier, Romain Aucagne, Caroline Truntzer, Cyril Fournier, François Ghiringhelli, Caroline Chapusot, Laurent Martin, Anne Marie Bouvier, Sylvain Manfredi, Valérie Jooste, Mary B. Callanan and Côme Lepage
Cancers 2023, 15(1), 158; https://doi.org/10.3390/cancers15010158 - 27 Dec 2022
Cited by 7 | Viewed by 2294
Abstract
Stage II colon cancer (CC), although diagnosed early, accounts for 16% of CC deaths. Predictors of recurrence risk could mitigate this but are currently lacking. By using a DNA methylation-based clinical screening in real-world (n = 383) and in TCGA-derived cohorts of [...] Read more.
Stage II colon cancer (CC), although diagnosed early, accounts for 16% of CC deaths. Predictors of recurrence risk could mitigate this but are currently lacking. By using a DNA methylation-based clinical screening in real-world (n = 383) and in TCGA-derived cohorts of stage II CC (n = 134), we have devised a novel 40 CpG site-based classifier that can segregate stage II CC into four previously undescribed disease sub-classes that are characterised by distinct molecular features, including activation of MYC/E2F-dependant proliferation signatures. By multivariate analyses, hypermethylation of 2 CpG sites at genes CDH17 and LRP2, respectively, was found to independently confer either significantly increased (CDH17; p-value, 0.0203) or reduced (LRP2; p-value, 0.0047) risk of CC recurrence. Functional enrichment and immune cell infiltration analyses, on RNAseq data from the TCGA cohort, revealed cases with hypermethylation at CDH17 to be enriched for KRAS, epithelial-mesenchymal transition and inflammatory functions (via IL2/STAT5), associated with infiltration by ‘exhausted’ T cells. By contrast, LRP2 hypermethylated cases showed enrichment for mTORC1, DNA repair pathways and activated B cell signatures. These findings will be of value for improving personalised care paths and treatment in stage II CC patients. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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Graphical abstract

20 pages, 3013 KiB  
Article
Clinicopathological and Prognostic Value of Survivin Expression in Surgically Resected Pancreatic Ductal Adenocarcinoma
by Christian Vay, Shahrooz Babaei, Sami-Alexander Safi, Levent Dizdar, Alexander Rehders, Lena Haeberle, Christoph Roderburg, Sven H. Loosen, Irene Esposito, Wolfram T. Knoefel and Andreas Krieg
Cancers 2022, 14(14), 3494; https://doi.org/10.3390/cancers14143494 - 18 Jul 2022
Cited by 5 | Viewed by 2082
Abstract
Background: Survival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor. Thus, novel therapeutic concepts focus on the development of targeted therapies. In this context, inhibitor of apoptosis protein (IAP) survivin is regarded as a promising oncotherapeutic target. However, its expression and prognostic [...] Read more.
Background: Survival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor. Thus, novel therapeutic concepts focus on the development of targeted therapies. In this context, inhibitor of apoptosis protein (IAP) survivin is regarded as a promising oncotherapeutic target. However, its expression and prognostic value in different tumour compartments of PDAC have not been studied. Methods: Immunohistochemical analysis of survivin in different PDAC tumour compartments from 236 consecutive patients was correlated with clinicopathological variables and survival. Results: In comparison to healthy pancreatic tissue high nuclear (p < 0.001) and high cytoplasmic (p < 0.01) survivin expression became evident in the tumour centre, along the invasion front and in lymph node metastases. Cytoplasmic overexpression of survivin in tumour centres was related to the presence of distant metastasis (p = 0.016) and UICC III/IV stages (p = 0.009), while high cytoplasmic expression at the invasion front grouped with venous infiltration (p = 0.022). Increased nuclear survivin along the invasion front correlated with perineural invasion (p = 0.035). High nuclear survivin in tumour centres represented an independent prognostic factor for overall survival of pancreatic tail carcinomas (HR 13.5 95%CI (1.4–129.7)) and correlated with a limited disease-free survival in PDAC (HR 1.80 95%CI (1.04–3.12)). Conclusion: Survivin is associated with advanced disease stages and poor prognosis. Therefore, survivin will help to identify patients with aggressive tumour phenotypes that could benefit from the inclusion in clinical trials incorporating survivin inhibitors in PDAC. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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17 pages, 1470 KiB  
Article
DNA Methylation of Imprinted Genes KCNQ1, KCNQ1OT1, and PHLDA2 in Peripheral Blood Is Associated with the Risk of Breast Cancer
by Jinming Fu, Lei Zhang, Dapeng Li, Tian Tian, Xuan Wang, Hongru Sun, Anqi Ge, Yupeng Liu, Xianyu Zhang, Hao Huang, Shuhan Meng, Ding Zhang, Liyuan Zhao, Simin Sun, Ting Zheng, Chenyang Jia, Yashuang Zhao and Da Pang
Cancers 2022, 14(11), 2652; https://doi.org/10.3390/cancers14112652 - 27 May 2022
Cited by 9 | Viewed by 2490
Abstract
Methylation alterations of imprinted genes lead to loss of imprinting (LOI). Although studies have explored the mechanism of LOI in breast cancer (BC) development, the association between imprinted gene methylation in peripheral blood and BC risk is largely unknown. We utilized HumanMethylation450 data [...] Read more.
Methylation alterations of imprinted genes lead to loss of imprinting (LOI). Although studies have explored the mechanism of LOI in breast cancer (BC) development, the association between imprinted gene methylation in peripheral blood and BC risk is largely unknown. We utilized HumanMethylation450 data from TCGA and GEO (n = 1461) to identify the CpG sites of imprinted genes associated with BC risk. Furthermore, we conducted an independent case-control study (n = 1048) to validate DNA methylation of these CpG sites in peripheral blood and BC susceptibility. cg26709929, cg08446215, cg25306939, and cg16057921, which are located at KCNQ1, KCNQ1OT1, and PHLDA2, were discovered to be associated with BC risk. Subsequently, the association between cg26709929, cg26057921, and cg25306939 methylation and BC risk was validated in our inhouse dataset. All 22 CpG sites in the KCNQ1OT1 region were associated with BC risk. Individuals with a hypermethylated KCNQ1OT1 region (>0.474) had a lower BC risk (OR: 0.553, 95% CI: 0.397−0.769). Additionally, the methylation of the KCNQ1OT1 region was not significantly different among B cells, monocytes, and T cells, which was also observed at CpG sites in PHLDA2. In summary, the methylation of KCNQ1, KCNQ1OT1, and PHLDA2 was associated with BC risk, and KCNQ1OT1 methylation could be a potential biomarker for BC risk assessment. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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22 pages, 3522 KiB  
Article
Identification of Tissue-Specific Gene Clusters Induced by DNA Demethylation in Lung Adenocarcinoma: More Than Germline Genes
by Anna Diacofotaki, Axelle Loriot and Charles De Smet
Cancers 2022, 14(4), 1007; https://doi.org/10.3390/cancers14041007 - 16 Feb 2022
Cited by 4 | Viewed by 3121
Abstract
Genome-wide loss of DNA methylation is commonly observed in human cancers, but its impact on the tumor transcriptome remains ill-defined. Previous studies demonstrated that this epigenetic alteration causes aberrant activation of a germline-specific gene expression program. Here, we examined if DNA hypomethylation in [...] Read more.
Genome-wide loss of DNA methylation is commonly observed in human cancers, but its impact on the tumor transcriptome remains ill-defined. Previous studies demonstrated that this epigenetic alteration causes aberrant activation of a germline-specific gene expression program. Here, we examined if DNA hypomethylation in tumors also leads to de-repression of gene clusters with other tissue specificities. To this end, we explored transcriptomic and methylomic datasets from human lung adenocarcinoma (LUAD) cell lines, normal lung, and lung alveolar type II cells, considered as the origin of LUAD. Interestingly, DNA demethylation in LUAD cell lines was associated with activation of not only germline-specific (CG) genes, but also gene clusters displaying specific expression in the gastrointestinal tract (GI), or in stratified epithelia (SE). Consistently, genes from all three clusters showed highly specific patterns of promoter methylation among normal tissues and cell types, and were generally sensitive to induction by a DNA demethylating agent. Analysis of TCGA datasets confirmed that demethylation and activation of CG, GI and SE genes also occurs in vivo in LUAD tumor tissues, in association with global genome hypomethylation. For genes of the GI cluster, we demonstrated that HNF4A is a necessary factor for transcriptional activation following promoter demethylation. Interestingly, expression of several SE genes, in particular FAM83A, correlated with both tumor grade and reduced patient survival. Together, our study uncovers novel cell-type specific gene clusters that become aberrantly activated in LUAD tumors in association with genome-wide hypomethylation. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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Review

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29 pages, 1138 KiB  
Review
Epigenetics of Thymic Epithelial Tumors
by Vanessa Nicolì and Fabio Coppedè
Cancers 2023, 15(2), 360; https://doi.org/10.3390/cancers15020360 - 5 Jan 2023
Cited by 7 | Viewed by 2576
Abstract
Thymic epithelial tumors (TETs) arise from the epithelial cells of the thymus and consist in the 1% of all adult malignancies, despite the fact that they are the most common lesions of the anterior mediastinum. TETs can be divided mainly into thymomas, thymic [...] Read more.
Thymic epithelial tumors (TETs) arise from the epithelial cells of the thymus and consist in the 1% of all adult malignancies, despite the fact that they are the most common lesions of the anterior mediastinum. TETs can be divided mainly into thymomas, thymic carcinomas, and the rarest ad aggressive neuroendocrine forms. Despite the surgical resection is quite resolving, the diagnosis of TETs is complicated by the absence of symptoms and the clinical presentation aggravated by several paraneoplastic disorders, including myasthenia gravis. Thus, the heterogeneity of TETs prompts the search for molecular biomarkers that could be helpful for tumor characterization and clinical outcomes prediction. With these aims, several researchers investigated the epigenetic profiles of TETs. In this manuscript, we narratively review the works investigating the deregulation of epigenetic mechanisms in TETs, highlighting the need for further studies combining genetic, epigenetic, and expression data to better characterize the different molecular subtypes and identify, for each of them, the most relevant epigenetic biomarkers of clinical utility. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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27 pages, 2307 KiB  
Review
Histone Chaperones and Digestive Cancer: A Review of the Literature
by Zhou Zhao, Zhaolun Cai, Tianxiang Jiang, Junhong Han and Bo Zhang
Cancers 2022, 14(22), 5584; https://doi.org/10.3390/cancers14225584 - 14 Nov 2022
Cited by 3 | Viewed by 1911
Abstract
Background: The global burden of digestive cancer is expected to increase. Therefore, crucial for the prognosis of patients with these tumors is to identify early diagnostic markers or novel therapeutic targets. There is accumulating evidence connecting histone chaperones to the pathogenesis of digestive [...] Read more.
Background: The global burden of digestive cancer is expected to increase. Therefore, crucial for the prognosis of patients with these tumors is to identify early diagnostic markers or novel therapeutic targets. There is accumulating evidence connecting histone chaperones to the pathogenesis of digestive cancer. Histone chaperones are now broadly defined as a class of proteins that bind histones and regulate nucleosome assembly. Recent studies have demonstrated that multiple histone chaperones are aberrantly expressed and have distinct roles in digestive cancers. Objective: The purpose of this review is to present the current evidence regarding the role of histone chaperones in digestive cancer, particularly their mechanism in the development and progression of esophageal, gastric, liver, pancreatic, and colorectal cancers. In addition, the prognostic significance of particular histone chaperones in patients with digestive cancer is discussed. Methods: According to PRISMA guidelines, we searched the PubMed, Embase, and MEDLINE databases to identify studies on histone chaperones and digestive cancer from inception until June 2022. Results: A total of 104 studies involving 21 histone chaperones were retrieved. Conclusions: This review confirms the roles and mechanisms of selected histone chaperones in digestive cancer and suggests their significance as potential prognostic biomarkers and therapeutic targets. However, due to their non-specificity, more research on histone chaperones should be conducted in the future to elucidate novel strategies of histone chaperones for prognosis and treatment of digestive cancer. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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33 pages, 1515 KiB  
Review
DNA Methylation Biomarkers for Prediction of Response to Platinum-Based Chemotherapy: Where Do We Stand?
by Nuno Tiago Tavares, Saulė Gumauskaitė, João Lobo, Carmen Jerónimo and Rui Henrique
Cancers 2022, 14(12), 2918; https://doi.org/10.3390/cancers14122918 - 13 Jun 2022
Cited by 6 | Viewed by 3902
Abstract
Platinum-based chemotherapy is routinely used for the treatment of several cancers. Despite all the advances made in cancer research regarding this therapy and its mechanisms of action, tumor resistance remains a major concern, limiting its effectiveness. DNA methylation-based biomarkers may assist in the [...] Read more.
Platinum-based chemotherapy is routinely used for the treatment of several cancers. Despite all the advances made in cancer research regarding this therapy and its mechanisms of action, tumor resistance remains a major concern, limiting its effectiveness. DNA methylation-based biomarkers may assist in the selection of patients that may benefit (or not) from this type of treatment and provide new targets to circumvent platinum chemoresistance, namely, through demethylating agents. We performed a systematic search of studies on biomarkers that might be predictive of platinum-based chemotherapy resistance, including in vitro and in vivo pre-clinical models and clinical studies using patient samples. DNA methylation biomarkers predictive of response to platinum remain mostly unexplored but seem promising in assisting clinicians in the generation of more personalized follow-up and treatment strategies. Improved methodologies for their detection and quantification, including non-invasively in liquid biopsies, are additional attractive features that can bring these biomarkers into clinical practice, fostering precision medicine. Full article
(This article belongs to the Special Issue Cancer Epigenetic Biomarkers)
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