Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

Zhang, Wa; Klinkebiel, David; Barger, Carter J.; Pandey, Sanjit; Guda, Chittibabu; Miller, Austin; Akers, Stacey N.; Odunsi, Kunle; Karpf, Adam R.

doi:10.3390/cancers12030764

Cited by 52 publications

(27 citation statements)

References 88 publications

(160 reference statements)

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“…The association between global DNA hypomethylation and poor prognosis is usually linked to genomic instability [28,[62][63][64]. Almost 50% of the human genome is composed of transposable elements, which are silenced by hypermethylation in normal cells [65,66].…”

Section: Discussionmentioning

confidence: 99%

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

Camuzi¹,

Buexm²,

Lourenço

et al. 2021

Cancers

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HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements (TEs) are still missing. Here we performed pyrosequencing to evaluate a 5-CpG methylation signature and Line1 methylation in an oropharyngeal squamous cell carcinoma (OPSCC) cohort. We further evaluated the methylation levels of the TEs, their correlation with gene expression and their impact on overall survival (OS) using the TCGA cohort. In our dataset, the 5-CpG signature distinguished HPV-positive and HPV-negative OPSCC with 66.67% sensitivity and 84.33% specificity. Line1 methylation levels were higher in HPV-positive cases. In the TCGA cohort, Line1, Alu and long terminal repeats (LTRs) showed hypermethylation in a frequency of 60.5%, 58.9% and 92.3%, respectively. ZNF541 and CCNL1 higher expression was observed in HPV-positive OPSCC, correlated with lower methylation levels of promoter-associated Alu and LTR, respectively, and independently associated with better OS. Based on our findings, we may conclude that a 5-CpG methylation signature can discriminate OPSCC according to HPV status with high accuracy and TEs are differentially methylated and may regulate gene expression in HPV-positive OPSCC.

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Section: Discussionmentioning

confidence: 99%

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

Camuzi¹,

Buexm²,

Lourenço

et al. 2021

Cancers

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“…Global genome DNA hypomethylation (GGDHo) occurs in many cancers [132,133], except perhaps in acute lymphocytic leukemia [134]. Given the normal distribution of DNAm across the genome, GGDHo is mostly attributed to loss of methylation occurring in late-replicating heterochromatic domains and in intragenic regions [133,134]. The abundance of DNAm varies across the normal genome.…”

Section: Dna Hypomethylationmentioning

confidence: 99%

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Desaulniers

Vasseur

Jacobs

et al. 2021

IJMS

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Epigenetics involves a series of mechanisms that entail histone and DNA covalent modifications and non-coding RNAs, and that collectively contribute to programing cell functions and differentiation. Epigenetic anomalies and DNA mutations are co-drivers of cellular dysfunctions, including carcinogenesis. Alterations of the epigenetic system occur in cancers whether the initial carcinogenic events are from genotoxic (GTxC) or non-genotoxic (NGTxC) carcinogens. NGTxC are not inherently DNA reactive, they do not have a unifying mode of action and as yet there are no regulatory test guidelines addressing mechanisms of NGTxC. To fil this gap, the Test Guideline Programme of the Organisation for Economic Cooperation and Development is developing a framework for an integrated approach for the testing and assessment (IATA) of NGTxC and is considering assays that address key events of cancer hallmarks. Here, with the intent of better understanding the applicability of epigenetic assays in chemical carcinogenicity assessment, we focus on DNA methylation and histone modifications and review: (1) epigenetic mechanisms contributing to carcinogenesis, (2) epigenetic mechanisms altered following exposure to arsenic, nickel, or phenobarbital in order to identify common carcinogen-specific mechanisms, (3) characteristics of a series of epigenetic assay types, and (4) epigenetic assay validation needs in the context of chemical hazard assessment. As a key component of numerous NGTxC mechanisms of action, epigenetic assays included in IATA assay combinations can contribute to improved chemical carcinogen identification for the better protection of public health.

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“…In addition to genetic mutations, epigenetic alterations have also been described in OC, comprising both global DNA hypomethylation and gene-specific hypermethylation. While passive DNA hypomethylation associated with genetic instability and poor prognosis has been detected as blocks in late-replicating and repressed regions [30], specific hypermethylation of CpG sites at gene promoters affects specific tumor suppressor genes such as SLIT2, PTEN, OPCML, RASSF1A, p16, MLH1, E-cadherin or APC [31].…”

Section: Origin and Molecular Features Of Ocmentioning

confidence: 99%

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

Muñoz-Galván

Carnero

2020

Cells

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Ovarian cancer is the most lethal gynecological malignancy due to its late detection and high recurrence rate. Resistance to conventional platinum-based therapies and metastasis are attributed to a population of cells within tumors called cancer stem cells, which possess stem-like features and are able to recapitulate new tumors. Recent studies have deepened the understanding of the biology of ovarian cancer stem cells and their special properties and have identified multiple markers and signaling pathways responsible for their self-renewal abilities. Targeting cancer stem cells represents the most promising strategy for overcoming therapy resistance and reducing mortality in ovarian cancer, but further efforts must be made to improve our understanding of the mechanisms involved in therapy resistance. In this review, we summarize our current knowledge about ovarian cancer stem cells, their involvement in metastasis and their interactions with the tumor microenvironment; we also discuss the therapeutic approaches that are being developed to target them to prevent tumor relapse.

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Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

Cited by 52 publications

References 88 publications

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer

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