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:10.1101/2020.01.22.20018374

Cited by 215 publications

(436 citation statements)

References 79 publications

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“…have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50].…”

Section: Of 35mentioning

confidence: 99%

“…Besides hypermethylation, global DNA hypomethylation due to decreased levels of 5-methyl-deoxycytidine (5mdC) has been shown in cancer [48]. Global DNA hypomethylation usually occurs at the repetitive elements of the genome, including the interspersed retrotransposon LINE-1 [48], which makes up approximately 17% of human genome. In that context, hypomethylation of LINE-1 has been reported in OC [48].…”

Section: Epigenetic Changesmentioning

confidence: 99%

“…Global DNA hypomethylation usually occurs at the repetitive elements of the genome, including the interspersed retrotransposon LINE-1 [48], which makes up approximately 17% of human genome. In that context, hypomethylation of LINE-1 has been reported in OC [48]. In addition, it has been shown that hypomethylation is a common event in STICs, the precursor lesion of HGSOC [48].…”

Section: Epigenetic Changesmentioning

confidence: 99%

“…In that context, hypomethylation of LINE-1 has been reported in OC [48]. In addition, it has been shown that hypomethylation is a common event in STICs, the precursor lesion of HGSOC [48]. Global DNA hypomethylation has also been reported in OC [48], and has been linked with advanced-stage disease and reduced overall and disease-free survival [48].…”

Section: Epigenetic Changesmentioning

confidence: 99%

“…In addition, it has been shown that hypomethylation is a common event in STICs, the precursor lesion of HGSOC [48]. Global DNA hypomethylation has also been reported in OC [48], and has been linked with advanced-stage disease and reduced overall and disease-free survival [48]. Significantly enhanced levels of hypomethylation of satellite DNA cytometry [72].…”

Section: Epigenetic Changesmentioning

confidence: 99%

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Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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Epithelial ovarian cancer (EOC) constitutes 90% of ovarian cancers (OC) and is the eighth most common cause of cancer-related death in women. The cancer histologically and genetically is very complex having a high degree of tumour heterogeneity. The pathogenic variability in OC causes significant impediments in effectively treating patients, resulting in a dismal prognosis. Disease progression is predominantly influenced by the peritoneal tumour microenvironment rather than properties of the tumor and is the major contributor to prognosis. Standard treatment of OC patients consists of debulking surgery, followed by chemotherapy, which in most cases end in recurrent chemoresistant disease. This review discusses the different origins of high-grade serous ovarian cancer (HGSOC), the major sub-type of EOC. Tumour heterogeneity, genetic/epigenetic changes, and cancer stem cells (CSC) in facilitating HGSOC progression and their contribution in the circumvention of therapy treatments are included. Several new treatment strategies are discussed including our preliminary proof of concept study describing the role of mitochondria-associated granulocyte macrophage colony-stimulating factor signaling protein (Magmas) in HGSOC and its unique potential role in chemotherapy-resistant disease. of 35have been observed in OC patients but not in patients with benign and borderline tumours, and this hypomethylation correlates with advanced-stage disease and poor prognosis [48,49]. A genome-wide methylation profiling of blood cells from healthy controls and age-matched untreated OC patients identified CpG methylation of 2714 cancer-related genes, of which 56% were hypomethylated [50]. Ovarian Cancer Stem CellsCellular heterogeneity associated with genetic and epigenetic changes in tumours are linked with the initiation and expansion of CSCs, a population of cells within the tumour, which initiate tumour growth through self-renewal and differentiation processes [51,52]. These cells are more adaptive to the changing tumour microenvironment and tend to be more resistant to treatment. CSCs are highly plastic and a few numbers of isolated CSCs have been shown to be responsible for tumorgenesis and are more chemotherapy and radiation resistant due to their dormant state and a high expression of drug efflux pumps [53,54]. As a result, CSCs are able to adapt to different tumour microenvironments and survive due to their efficient DNA repair mechanisms and their capacity to evade host immune surveillance [55][56][57]. These inherent properties of CSCs suggest an active role in tumour relapse and emphasize the need to develop effective targeted therapies to improve clinical outcomes in patients [51][52][53][54][55][56][57].Stem cells have been identified in ovaries and fallopian tubes [58,59]. These cells express proteins including aldehyde dehydrogenase family 1 A2 (ALDH1A2), homeobox protein NANOG, LIM homeobox protein 9 (LHX9) and frizzled-related protein 1 (SRFP1) and have been observed in OSE, CIC and fimbria [2,[58][59][60][61][62]. In a...

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Section: Of 35mentioning

confidence: 99%

Section: Epigenetic Changesmentioning

confidence: 99%

Section: Epigenetic Changesmentioning

confidence: 99%

Section: Epigenetic Changesmentioning

confidence: 99%

Section: Epigenetic Changesmentioning

confidence: 99%

See 3 more Smart Citations

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ahmed

Kadife²,

Raza

et al. 2020

Cells

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Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations

Nguyen

Cao

Nguyen

et al. 2021

Sci Rep

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Targeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC). However, resistance to TKI almost always develops after treatment. Although genetic and epigenetic alterations have each been shown to drive resistance to TKI in cell line models, clinical evidence for their contribution in the acquisition of resistance remains limited. Here, we employed liquid biopsy for simultaneous analysis of genetic and epigenetic changes in 122 Vietnamese NSCLC patients undergoing TKI therapy and displaying acquired resistance. We detected multiple profiles of resistance mutations in 51 patients (41.8%). Of those, genetic alterations in EGFR, particularly EGFR amplification (n = 6), showed pronounced genome instability and genome-wide hypomethylation. Interestingly, the level of hypomethylation was associated with the duration of response to TKI treatment. We also detected hypermethylation in regulatory regions of Homeobox genes which are known to be involved in tumor differentiation. In contrast, such changes were not observed in cases with MET (n = 4) and HER2 (n = 4) amplification. Thus, our study showed that liquid biopsy could provide important insights into the heterogeneity of TKI resistance mechanisms in NSCLC patients, providing essential information for prediction of resistance and selection of subsequent treatment.

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Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

et al. 2021

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Genetic mutations or regulatory failures underlie cellular malfunction in many diseases, including colorectal cancer and inflammatory bowel diseases. However, mutational defects alone fail to explain the complexity of such disorders. Epigenetic regulation-control of gene action through chemical and structural changes of chromatin-provides a platform to integrate multiple extracellular inputs and prepares the cellular genome for appropriate gene expression responses. Coregulation by polycomb repressive complex 2-mediated trimethylation of lysine 27 on histone 3 and DNA methylation has emerged as one of the most influential epigenetic controls in colorectal cancer and many other diseases, but molecular details remain inadequate. Here we review the molecular interplay of these epigenetic features in relation to gastrointestinal development, homeostasis, and disease biology. We discuss other epigenetic mechanisms pertinent to the balance of trimethylation of lysine 27 on histone 3 and DNA methylation and their actions in gastrointestinal cancers. We also review the current molecular understanding of chromatin control in the pathogenesis of inflammatory bowel diseases.

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Global DNA hypomethylation in epithelial ovarian cancer: passive demethylation and association with genomic instability

Cited by 215 publications

References 79 publications

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

Liquid biopsy uncovers distinct patterns of DNA methylation and copy number changes in NSCLC patients with different EGFR-TKI resistant mutations

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

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