Chronic Inflammation to Cancer: The Impact of Oxidative Stress on DNA Methylation

Abstract

The genomic landscape of cancer cells is complex and heterogeneous, with aberrant DNA methylation being a common observation. Growing evidence indicates that oxidants produced from immune cells may interact with epigenetic processes, and this may represent a mechanism for the initiation of altered epigenetic patterns observed in both precancerous and cancerous cells. Around 20% of cancers are linked to chronic inflammatory conditions, yet the precise mechanisms connecting inflammation with cancer progression remain unclear. During chronic inflammation, immune cells release oxidants in response to stimuli, which, in high concentrations, can cause cytotoxic effects. Oxidants are known to damage DNA and proteins and disrupt normal signalling pathways, potentially initiating a sequence of events that drives carcinogenesis. While research on the impact of immune cell-derived oxidants on DNA methylation remains limited, this mechanism may represent a crucial link between chronic inflammation and cancer development. This review examines current evidence on inflammation-associated DNA methylation changes in cancers related to chronic inflammation.

Graphical abstract

Keywords

inflammation / cancer / epigenetics / DNA methylation / oxidative stress

1. Introduction

The link between chronic inflammation and cancer is well established, however, the molecular mechanisms connecting these processes remain unclear. Disruptions in the integrity or expression of tumour suppressor genes and proto-oncogenes significantly contribute to cancer initiation and progression [1]. Although mutational events in cancer are well-researched, the role of epigenetic modifications in disease onset and development is less understood and remains an active area of investigation. In cancers associated with chronic inflammation, common epigenetic alterations include hypermethylation of tumor suppressor gene promoters and global hypomethylation of oncogenes [2]. During inflammation, immune cells release oxidants in response to pathogens or irritants and prolonged exposure to these oxidants in chronic inflammation can damage surrounding cells. However, the subtler impacts of oxidants, particularly on epigenetic processes, are less understood. This review examines the evidence for a mechanistic link between oxidants and altered DNA methylation patterns in the context of chronic inflammation and cancer.

2. DNA Methylation

Epigenetics is the study of heritable gene expression changes that occur without altering the underlying DNA sequence [3]. DNA methylation, the most extensively studied epigenetic modification, involves the addition of a methyl group to the 5th carbon of the pyrimidine ring in cytosine-guanine (CpG) dinucleotides, resulting in the modified base 5-methylcytosine [4]. DNA methyltransferases (DNMTs) facilitate this process by binding to CpG sites and catalysing the transfer of a methyl group from S-adenosyl methionine (SAM) [5]. Typically, methylated DNA leads to gene silencing by blocking transcriptional proteins, including RNA polymerase, from binding [6]. Additionally, methylated DNA can recruit methyl-CpG-binding domain proteins that direct the assembly of transcriptional complexes, such as histone deacetylases and chromatin remodeling proteins, leading to condensed, inactive chromatin [7, 8].

DNA methylation patterns are largely established during embryonic development and remain stable throughout the cell’s life, with approximately 60–80% of methylated CpG sites found within gene bodies in humans [9]. However, a subset of CpG regions display dynamic methylation levels and are influenced by factors including age [10], diet [11, 12], smoking [13], exercise [14], drug use [15], and alcohol consumption [16]. One of the most dynamic regions are CpG dense regions known as ‘CpG islands’. CpG islands are genomic features tightly associated with gene promoters and generally exist in an unmethylated state, which allows for open chromatin that is accessible for transcription [17].

DNA demethylation is crucial for maintaining biological functions, including gene regulation, cell differentiation and genomic stability [18, 19, 20]. This process is mediated by distinct DNMT enzymes, each with specific biological functions. DNMT1 maintains methylation patterns during cell division by recognising hemimethylated DNA and adding methyl groups to the nascent strand, ensuring faithful inheritance of methylation patterns across cell divisions [21]. DNMT3a and DNMT3b catalyses de novo methylation adding new methylation groups during cell division [22], while DNMT2 methylates transfer RNA, impacting protein translation [23].

Demethylation can be passive or active. Passive demethylation occurs when DNMT1 fails to methylate a nascent daughter strand, or if SAM synthesis pathways are disrupted [24]. Active demethylation is mediated by the ten-eleven translocation (TET) protein family (TET1, TET2, TET3), which oxidises 5-methylcytosine to 5-hydroxymethyl cytosine (5-hmC) using molecular oxygen, iron (Fe(II)), and \alpha-ketoglutarate (\alphaKG) as cofactors [25]. Further oxidation by TET enzymes can convert 5-hmC into 5-formylcytosine and 5-carboxycytosine [26]. 5-hmC is abundant in the genomic DNA of mammals and has emerged as a potentially stable epigenetic marker, referred to as the “sixth base”, due to its suggested role as more than an intermediate in demethylation [27]. Additionally, TET and activation-induced cytidine deaminase (AID) enzymes are thought to convert 5-hmC to 5-hydroxymethyluracil, further promoting active demethylation [25].

3. Understanding the Relationship between Inflammation and Cancer

Cancer fundamentally arises from cumulative genetic changes that enable abnormal cell behavior. These changes, summarized in the “hallmarks of cancer”, include sustaining proliferative signals, evading growth suppressors, resisting cell death, achieving replicative immortality, accessing blood supply, activating invasion and metastasis, reprogramming metabolism, avoiding immune detection, genome instability and mutation and tumour-promoting inflammation [28].

Chronic inflammation is characterised by prolonged immune cell activation and release of inflammatory molecules that persist after the initial threat has subsided [29]. Chronic inflammation can arise from factors such as persistent infections [30], autoimmune disorders [31], long-term exposure to irritants [32]and unresolved acute inflammation. In these conditions, immune regulation fails, and the mechanisms that would typically resolve the inflammatory response fail. This continuous immune activity harms surrounding tissues due to the sustained presence of cytotoxic molecules [33, 34].

The interplay between inflammation and cancer is complex and context-dependent [35, 36]. While acute inflammation can recruit cytotoxic T cells that target abnormal cells and may counteract cancer, chronic inflammation in established tumors often promotes progression. Continuous signalling within the tumor microenvironment exacerbates growth, angiogenesis, and metastasis [37, 38]. Inflammation can also be triggered by toll-like receptor (TLR) activation by microbial components, with varying effects. For example, TLR4 can promote intestinal tumors, while TLR2 appears protective in colitis-associated cancer [39, 40, 41].

Pro-inflammatory cytokines such as interleukins-6 and 8 (IL-6 and IL-8), tumour necrosis factor alpha (TNF-\alpha), and chemokines like C-C motif ligand 2 (CCL2) and CXC motif ligand 8 (CXL8) are frequently elevated in cancer, supporting tumor growth, blood vessel formation, and metastasis [42]. Transcription factors like nuclear factor kappa B (NF-\kappaB) and signal transducer and activator of transcription 3 (STAT3), which are often upregulated in cancer, enhance cell survival, proliferation, and immune evasion, further contributing to tumor development [43, 44]. Understanding the mechanisms by which inflammation drives carcinogenesis offers valuable insights for cancer prevention, diagnosis, treatment, and management.

4. Oxidative Stress

Under non-inflammatory conditions, reactive oxygen species (ROS) play an important role in modulating cell signalling pathways and in the regulation of homeostasis [45]. However, immune cells release a range of oxidants during the immune response, whereby they can exert cytotoxic effects [46]. Oxidative stress arises when the generation of oxidants surpasses the cell’s antioxidant defences [47]. Prolonged exposure to oxidative stress can damage DNA, alter the function of lipids and proteins, and activate transcription factors that up-regulate or down-regulate key molecular pathways [48]. Oxidants can directly react with DNA bases, forming adducts that cause mutations and base pair mismatches [49]. They can also induce double stranded breaks and cross-links that alter DNA structure and function, ultimately leading to genomic instability, mutations and chromosomal aberrations [50].

Oxidative stress is implicated in several disease states including every stage of carcinogenesis [51]. Cancer cells exhibit abnormal redox homeostasis, and maintaining high levels of oxidants along with immune infiltration that supports tumour cell proliferation [52]. While oxidative stress is damaging to normal cells, cancer cells adapt by upregulating antioxidant defences, enabling them to thrive under increased oxidative conditions [51].

Neutrophils, the most abundant immune cell, are a major source of ROS during the immune response. The production of superoxide (O₂^–) occurs inside the neutrophil phagosome through the action of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase 2 (NOX2) as part of a process known as the respiratory burst (Fig. 1) [53]. O₂^– spontaneously dismutates to form hydrogen peroxide (H₂O₂), that can further react with intracellular chloride ions to form hypochlorous acid (HOCl) [54] via the neutrophil enzyme myeloperoxidase (MPO). HOCl readily reacts with amines to yield chloramines, which have a greater diffusion rate and are longer-lived compared to other oxidants [55, 56]. Under certain conditions, neutrophils can form neutrophil extracellular traps (NETs), that are mesh-like structures containing DNA, histones and peptides capable of trapping and degrading pathogens [57]. Oxidants derived from NOX2 are involved in the signalling cascade leading to the NET formation and the release of oxidants into the extracellular environment, where they contribute to immune defence and can influence the surrounding tissue microenvironment [58].

5. Oxidant Directed Induction of Aberrant DNA Methylation

Oxidants can disrupt epigenetic regulation [56], with consequences for genomic stability and cancer development. Global DNA hypomethylation, particularly of oncogenes [59], is linked to increased mutation rates, genomic instability, and activation of carcinogenic pathways, while hypermethylation in CpG islands of tumor suppressor promoters is associated with gene silencing and impaired cell cycle control [60].

Oxidative damage can alter DNA bases, producing lesions such as 8-hydroxyl-2-deoxyguanosine (8-oxo-dG), 8-hydroxyguanine (8-oxoG), and O⁶-methylguanine, which are common in cancer and can interfere with DNA methylation patterns during DNA synthesis [61, 62]. For example, an in vitro study demonstrated that 8-oxoG can physically block DNMT1 from transferring methyl groups to neighbouring CpG sites. O⁶-methylguanine, further contributes to DNA hypomethylation by inhibiting DNMT binding and pairing incorrectly with thymine [63, 64].

Oxidant-induced hypomethylation may also result from DNMT1 inhibition. For example, glycine chloramine (GlyCl), produce through the reaction of HOCl with glycine [65, 66], can oxidize the DNMT1 active site and deplete the SAM precursor methionine, leading to a global decrease in DNA methylation and subsequent differential gene expression [65]. In studies with GlyCl-treated tissue cell lines, hypomethylation was enriched in cancer and inflammation-associated genes and concentrated at chromosomal ends, suggesting effects on chromosome stability and telomere length, both of which are common in cancer [66, 67] (Fig. 1). Significant genome-wide DNA methylation changes were also observed when T-lymphoma cells were exposed to sublethal levels of H₂O₂, which persisted after several rounds of cell division. This implies that oxidative stress can contribute to epigenetic heterogeneity often observed in the tumour microenvironment, which could have implications for long-term changes in gene expression [68]. Similarly, the reaction of HOCl with cytosine can result in the formation of 5-chlorocytosine, which mimics 5-methylcytosine and misguides methylation-sensitive proteins, leading to inappropriate methylation [69]. This results in the inappropriate methylation of habitually unmethylated CpG sites [70] and has been linked to promoter hypermethylation and gene silencing, such as observed in the hamster hprt gene [71].

Blocking the reduction of Fe(III) to Fe(II) through the exposure to H₂O₂ may reduce TET activity, and consequently 5-hmC [72], which has been observed in cells exposed to H₂O₂ over several days [72]. The conversion of 5-mC to 5-hmC by acetylated TET enzymes may normally protect against oxidative stress induced hypermethylation [73]. However, recent evidence suggests that oxidative stress may also alter TET enzyme function and thereby dysregulate DNA demethylation processes. In this instance, exposure to NaAsO₂ (arsenic containing compound) was found to induce oxidative stress and inhibit the activity of TET enzymes and subsequent demethylation processes in lung cells [74]. 5-hmC quantification by dot-blot and cell imaging has revealed that global 5-hmC levels are lower in some inflammation-associated cancers, including hepatocellular carcinoma and skin cancer, when compared with adjacent healthy tissues [75]. Corresponding TET gene expression in these tumours is also decreased, suggesting these epigenetic patterns are likely TET-mediated [75].

6. Aberrant DNA Methylation Patterns in Inflammatory Diseases and Associated Cancers

In this section, we explore aberrant DNA methylation patterns in cancers with strong associations with chronic inflammation. Although many other cancers are linked to chronic inflammation (summarised in Table 1, Ref. [76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115]), we have focused on those with both well-documented connections to sustained inflammatory states and significant epigenetic modifications, highlighting the critical role of inflammation in driving epigenetic changes during tumorigenesis.

6.1. Hepatitis C and Liver Cancer

Hepatitis C infection and hepatocellular carcinoma are strongly linked, and it is possible that alterations in epigenetic patterns might predispose this common form of liver cancer [116]. Hepatitis C virus (HCV) is a single-stranded RNA virus that replicates in hepatocytes. Infection induces a CD8 + T cell response, but in many cases the response is not successful in clearing the virus, resulting in chronic inflammation [117]. Additionally, HCV proteins induce activation and further increase oxidant levels and inflammatory responses, including NF-\kappaB and STAT3 activation [118]. Chronic hepatitis due to HCV infection is highly associated with hepatocellular carcinoma, whereby the incidence rate is correlated with the duration of HCV infection [119]. HCV can directly impact cellular DNA repair and proliferation, however, hepatocellular carcinoma may additionally be driven by persistent immune response [120]. Only a small number of hepatocytes contain detectable HCV, which is still associated with a high rate of hepatocellular turnover because the immune system and/or the virus induces apoptosis of infected cells, which are then replaced by hepatocellular proliferation [120].

It has been observed that oxidant exposure can mediate the bidirectional regulation of several genes that code for enzymes related to de novo methylation in hepatocellular carcinoma. In particular, one study demonstrated the effect of H₂O₂ on DNA methylation levels in the promoter of E-cadherin [6], a tumour suppressor gene responsible for maintaining epithelial integrity and tissue architecture [121]. Loss of E-cadherin expression may be a key driver of metastasis due to the depletion of cellular adhesion mechanisms [122]. In hepatocellular carcinoma, H₂O₂exposure up-regulated the expression of the transcription factor ‘Snail’, which recruited key enzymes involved in closed chromatin-associated epigenetic modification to E-cadherin: Histone deacetylase 1, DNMT1 and methyl CpG binding protein 2 [123, 124]. This was correlated with E-cadherin silencing and inactivation of its function as a tumour suppressor [6]. It has also been observed that H₂O₂ exposure can increase levels of 8-oxo-dG in hepatocellular carcinoma cell lines, causing hypermethylation of 11 specific tumour suppressor genes involved in human hepatocarcinogenesis [125]. Furthermore, increased levels of 8-oxo-dG were strongly correlated with the presence of repressive histone markers and an overall state of condensed chromatin [125].

6.2 H. pylori and Gastric Cancer

H. pylori infection is strongly associated with the development of gastric cancer [126]. Chronic gastritis, caused by persistent inflammation due to H. pylori infection, can lead to alterations in the gastric mucosa, setting the stage for intestinal metaplasia and subsequent neoplastic transformation [127, 128]. The mucosa in H. pylori induced gastritis has increased levels of neutrophils, macrophages and inflammatory mediators such as cytokines and interleukins [129], accompanied by the release of oxidants that are known to cause genomic and epigenomic instability in gastric epithelia [126]. In H. pylori-infected Mongolian gerbils, hypermethylation was observed in gastric mucosae from infected animals, which correlated with the duration of infection [130]. H. pylori eradication led to a decrease in DNA methylation levels at specific genes, however, hypermethylation levels persisted even after H. pylori eradication [131].

Demethylation agents such as 5-Aza-2-deoxycytidine have been shown to reduce methylation induced by gastritis and prevent gastric cancer in gerbils [130]. Interestingly, gastritis-induced hypermethylation was inhibited upon treatment with an immunosuppressive agent, suggesting that H. pylori-induced inflammation was an important factor in the induction of aberrant DNA methylation [132, 133]. In a complementary study, it was shown that H. pylori infected macrophages co-incubated with gastric epithelial cells were able to yield a significant amount of nitric oxide, which induced methylation at the RUNX3 gene through a presumably, unknown mechanism. These findings were supported by similar methylation changes following lipopolysaccharide exposure and the inhibition of nitric, which blocked these effects [134].

In human studies, individuals infected with H. pylori show significantly higher methylation levels across various genes in the gastric mucosa compared to uninfected individuals with gastric cancer [135, 136, 137, 138, 139, 140]. Cell pathways likely to be affected in H. pylori-induced hypermethylation are cell adhesion genes (CDH1, VEZT, Cx32) [135, 136, 137], cell cycle regulators (CDKN2A) [138], DNA mismatch repair genes (MHL1) [139], and inflammation genes (TFF2, COX-2) [138, 140]. These epigenetic changes contribute to the disruption of normal cellular functions, promoting a microenvironment conducive to carcinogenesis.

6.3. Inflammatory Bowel Diseases and Colorectal Cancer

The gastrointestinal tract hosts a complex community of microorganisms and is exposed to various chemical agents through diet. Inflammatory bowel diseases (IBD), including of Crohn’s disease and ulcerative colitis, are characterised by chronic inflammation of the gastrointestinal tract and are highly associated with an increased risk of colitis-associated colorectal cancer (CAC) [141]. Like sporadic colorectal cancer, CAC develops due to genetic and epigenetic changes accumulated in dysplasia-associated lesions of the mucosa [142]. One study using a mouse model of colitis found that it led to an increase in intestinal tumours, reflective of how chronic inflammation in human IBD can promote cancer development [143]. Mice with inflammatory bowel disease exhibit oxidant-induced accumulation of 8-oxo-dG in colon epithelial cells, suggesting oxidants are abundant in the intestinal inflammatory environment [144]. In support of this, MPO and calprotectin have shown promise as faecal biomarkers of IBD, indicating that MPO is abundantly present and implies that other MPO-derived oxidants may be present in the IBD microenvironment [145, 146]. It has been shown that the methylation profile of tumours in CAC vs sporadic colorectal cancer (CRC) differ, which suggests that inflammation may play a key role in DNA methylation patterning [142]. Additionally, many genes have been shown to be differentially methylated in IBD patients compared to control patients [147]. IBD is further associated with serrated polyps in the bowel, which can develop into serrated polyposis syndrome (SPS), a condition characterised by multiple serrated lesions in the colon that are at a high risk for becoming cancerous. In a study that performed methylome analysis on SPS samples vs normal mucosa, it was found that the gene promoters HLA-F, SLFN12, HLA-DMA and RARRES3 were hypermethylated [148]. It was concluded that HLA-F hypermethylation is a novel biomarker candidate for SPS, and from a clinical viewpoint may be useful for identifying IBD patients that are more likely to develop the condition [148].

The role of oxidative stress in colorectal cancer progression has been illustrated in studies using human colorectal cancer cell lines and colitis models. Treatment of a human colorectal cancer cell line with H₂O₂ led to the upregulation of DNMT1 [149]. This increased the binding of DNMT1 to HDAC and presumably increased methylation in the promoter of the tumour suppressor gene, RUNX3, a gene that is commonly silenced across multiple different cancers [149]. This effect was reversed by treatment with the oxidant scavenger, N-acetylcysteine, suggesting that oxidants silenced RUNX3 expression via an epigenetic mechanism that may be associated with the progression of colorectal cancer [149]. Furthermore, oxidative stress induced by H₂O₂ in a mouse colitis model caused recruitment of DNMT1 to damaged chromatin, and also delocalised proteins involved in a repressive polycomb complex (DNMT1, histone deacetylase (sirtuin-1), and histone methyltransferase) from a non-CpG-rich region to CpG island-containing promoters carrying 8-oxo-dG [149]. These findings suggest that the oxidative stress induced by H₂O₂ could cause relocalisation of a silencing complex to oxidative damaged areas of tumour suppressor genes, and explain a mechanism for aberrant DNA methylation correlated with DNA damage and transcriptional silencing [150].

6.4. UV Exposure and Skin Cancer

Skin cancer has one of the most well-established relationships with environmental exposures, with ultraviolet (UV) radiation accounting for approximately 75% of melanomas and 90% of non-melanoma skin cancers [151]. Epidemiological and experimental evidence indicate that chronic inflammation is a key process in skin cells upon UV exposure, with key inflammatory mediators such as NF-\kappaB and STAT3 being instrumental in skin cancer pathogenesis [152]. UV exposure triggers significant immune infiltration into the skin that correlates with genetic and epigenetic changes.

DNA methylation changes in response to UVB radiation in mouse skin epidermis have been observed, including changes in the expression of genes that are known to be involved in skin carcinogenesis [153]. For instance, melanoma patients often display hypermethylation of promoters in several tumour suppressor genes including p16, E-cadherin, APC and TNF [154]. Conversely, DNA hypomethylation is thought to be related to melanoma pathogenesis, as the melanoma antigen gene is associated with decreased levels of methylation [155].

During the response to oxidative damage, hypermethylation occurs at genes linked to an increased risk of melanoma. Elevated oxidant levels in melanocytes have been associated with upregulation of DNMT1 and DNMT3b, leading to widespread promoter hypermethylation, thereby suggesting a connection between oxidative stress and changes in DNA methylation within melanoma [156]. Further studies have shown that carcinogenic processes in melanoma are greatly decreased by substances that have oxidant inhibiting qualities, such as genistein [157] and curcumin [158]. Genistein, in particular, has been shown to regulate DNA methylation pathways and affect tumour-related gene expression [159]. Additionally, melanocyte deadhesion, a key process in melanogenesis, results in both an increase in superoxide anion levels and DNMT1 production, leading to hypermethylation across multiple gene promoters [160]. Furthermore, it has been demonstrated that UVA induces the production of oxidants that cause DNA damage, including 8-OHdG [161], making it plausible that such oxidative damage would lead to alterations in the methylation profiles of exposed skin cells.

7. Conclusions

The high incidence of inflammation-associated cancers highlights the importance of understanding the molecular mechanisms that drive carcinogenesis. Although links between inflammation and cancer are established, the specific role of oxidants in altering DNA methylation patterns has received limited attention. Consequently, our understanding of the molecular processes linking oxidative stress and inflammation-related cancer remains incomplete, leaving unanswered questions about whether the DNA methylation changes induced by oxidants are causal or merely correlative. Aberrant DNA methylation patterns could act as primary drivers of carcinogenesis or represent secondary changes resulting from other cellular processes. Regardless, characterising these changes will aid in the development of biomarkers for disease development and progression. Due to their reversible nature, epigenetic factors also offer promising targets for precision therapies, potentially improving clinical outcomes.

Future research should prioritise identifying mechanisms behind oxidant-induced DNA methylation changes and exploring therapeutic strategies to counteract them. This focus will enhance both prevention and treatment outcomes for inflammation-associated malignancies. While many studies have examined the effect of oxidative stress, DNA methylation and inflammation as separate factors in cancer pathology, few have integrated them into a cohesive molecular pathway. Investigating this interplay could reveal novel insights and therapeutic opportunities in the field of cancer research.

References

[1] Kontomanolis EN, Koutras A, Syllaios A, Schizas D, Mastoraki A, Garmpis N, et al. Role of Oncogenes and Tumor-suppressor Genes in Carcinogenesis: A Review. Anticancer Research. 2020; 40: 6009–6015. https://doi.org/10.21873/anticanres.14622.

[2] Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene. 2002; 21: 5400–5413. https://doi.org/10.1038/sj.onc.1205651.

[3] Kato K. What is epigenetics? In Inflammation and Oral Cancer (pp. 79–100). Elsevier: the Netherlands. 2022.

[4] Dhar GA, Saha S, Mitra P, Nag Chaudhuri R. DNA methylation and regulation of gene expression: Guardian of our health. The Nucleus: an International Journal of Cytology and Allied Topics. 2021; 64: 259–270. https://doi.org/10.1007/s13237-021-00367-y.

[5] Lu SC. S-Adenosylmethionine. The International Journal of Biochemistry & Cell Biology. 2000; 32: 391–395. https://doi.org/10.1016/s1357-2725(99)00139-9.

[6] Lim SO, Gu JM, Kim MS, Kim HS, Park YN, Park CK, et al. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology. 2008; 135: 2128–2140, 2140.e1-8. https://doi.org/10.1053/j.gastro.2008.07.027.

[7] Freese K, Seitz T, Dietrich P, Lee SML, Thasler WE, Bosserhoff A, et al. Histone Deacetylase Expressions in Hepatocellular Carcinoma and Functional Effects of Histone Deacetylase Inhibitors on Liver Cancer Cells In Vitro. Cancers. 2019; 11: 1587. https://doi.org/10.3390/cancers11101587.

[8] Milazzo G, Mercatelli D, Di Muzio G, Triboli L, De Rosa P, Perini G, et al. Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability. Genes. 2020; 11: 556. https://doi.org/10.3390/genes11050556.

[9] Hernando-Herraez I, Garcia-Perez R, Sharp AJ, Marques-Bonet T. DNA Methylation: Insights into Human Evolution. PLoS Genetics. 2015; 11: e1005661. https://doi.org/10.1371/journal.pgen.1005661.

[10] Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging. Aging Cell. 2015; 14: 924–932. https://doi.org/10.1111/acel.12349.

[11] Maugeri A, Barchitta M. How Dietary Factors Affect DNA Methylation: Lesson from Epidemiological Studies. Medicina (Kaunas, Lithuania). 2020; 56: 374. https://doi.org/10.3390/medicina56080374.

[12] Stevens AJ, Rucklidge JJ, Darling KA, Eggleston MJ, Pearson JF, Kennedy MA. Methylomic changes in response to micronutrient supplementation and MTHFR genotype. Epigenomics. 2018; 10: 1201–1214. https://doi.org/10.2217/epi-2018-0029.

[13] Dugué PA, Jung CH, Joo JE, Wang X, Wong EM, Makalic E, et al. Smoking and blood DNA methylation: an epigenome-wide association study and assessment of reversibility. Epigenetics. 2020; 15: 358–368. https://doi.org/10.1080/15592294.2019.1668739.

[14] Fernández-Sanlés A, Sayols-Baixeras S, Castro DE Moura M, Esteller M, Subirana I, Torres-Cuevas S, et al. Physical Activity and Genome-wide DNA Methylation: The REgistre GIroní del COR Study. Medicine and Science in Sports and Exercise. 2020; 52: 589–597. https://doi.org/10.1249/MSS.0000000000002174.

[15] Osborne AJ, Pearson JF, Noble AJ, Gemmell NJ, Horwood LJ, Boden JM, et al. Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort. Translational Psychiatry. 2020; 10: 114. https://doi.org/10.1038/s41398-020-0800-3.

[16] Dugué PA, Wilson R, Lehne B, Jayasekara H, Wang X, Jung CH, et al. Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data. Addiction Biology. 2021; 26: e12855. https://doi.org/10.1111/adb.12855.

[17] Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes & Development. 2011; 25: 1010–1022. https://doi.org/10.1101/gad.2037511.

[18] Bhutani N, Burns DM, Blau HM. DNA demethylation dynamics. Cell. 2011; 146: 866–872. https://doi.org/10.1016/j.cell.2011.08.042.

[19] Cedar H, Sabag O, Reizel Y. The role of DNA methylation in genome-wide gene regulation during development. Development (Cambridge, England). 2022; 149: dev200118. https://doi.org/10.1242/dev.200118.

[20] Sriraman A, Debnath TK, Xhemalce B, Miller KM. Making it or breaking it: DNA methylation and genome integrity. Essays in Biochemistry. 2020; 64: 687–703. https://doi.org/10.1042/EBC20200009.

[21] Mohan KN. DNMT1: catalytic and non-catalytic roles in different biological processes. Epigenomics. 2022; 14: 629–643. https://doi.org/10.2217/epi-2022-0035.

[22] Gao L, Emperle M, Guo Y, Grimm SA, Ren W, Adam S, et al. Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms. Nature Communications. 2020; 11: 3355. https://doi.org/10.1038/s41467-020-17109-4.

[23] Goll MG. Biological role of the DNA methyltransferase homologue Dnmt2 in diverse eukaryotes. [PhD dissertation]. Columbia University. 2006.

[24] Dean W. Pathways of DNA demethylation. In DNA Methyltransferases-Role and Function (pp. 211–238). Springer: Germany. 2022.

[25] Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nature Reviews. Genetics. 2017; 18: 517–534. https://doi.org/10.1038/nrg.2017.33.

[26] Klungland A, Robertson AB. Oxidized C5-methyl cytosine bases in DNA: 5-Hydroxymethylcytosine; 5-formylcytosine; and 5-carboxycytosine. Free Radical Biology & Medicine. 2017; 107: 62–68. https://doi.org/10.1016/j.freeradbiomed.2016.11.038.

[27] Kriukienė E, Tomkuvienė M, Klimašauskas S. 5-Hydroxymethylcytosine: the many faces of the sixth base of mammalian DNA. Chemical Society Reviews. 2024; 53: 2264–2283. https://doi.org/10.1039/d3cs00858d.

[28] Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discovery. 2022; 12: 31–46. https://doi.org/10.1158/2159-8290.CD-21-1059.

[29] Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019; 25: 1822–1832. https://doi.org/10.1038/s41591-019-0675-0.

[30] Sadri Nahand J, Moghoofei M, Salmaninejad A, Bahmanpour Z, Karimzadeh M, Nasiri M, et al. Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: A review. International Journal of Cancer. 2020; 146: 305–320. https://doi.org/10.1002/ijc.32688.

[31] Dopkins N, Nagarkatti PS, Nagarkatti M. The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders. Immunology. 2018; 154: 178–185. https://doi.org/10.1111/imm.12903.

[32] Matsuzaki H, Maeda M, Lee S, Nishimura Y, Kumagai-Takei N, Hayashi H, et al. Asbestos-induced cellular and molecular alteration of immunocompetent cells and their relationship with chronic inflammation and carcinogenesis. Journal of Biomedicine & Biotechnology. 2012; 2012: 492608. https://doi.org/10.1155/2012/492608.

[33] Ferguson LR. Chronic inflammation and mutagenesis. Mutation Research. 2010; 690: 3–11. https://doi.org/10.1016/j.mrfmmm.2010.03.007.

[34] Schottenfeld D, Beebe-Dimmer J. Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA: a Cancer Journal for Clinicians. 2006; 56: 69–83. https://doi.org/10.3322/canjclin.56.2.69.

[35] Shalapour S, Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. The Journal of Clinical Investigation. 2015; 125: 3347–3355. https://doi.org/10.1172/JCI80007.

[36] Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology: Official Journal of the European Society for Medical Oncology. 2012; 23 Suppl 8: viii6–viii9. https://doi.org/10.1093/annonc/mds256.

[37] Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8⁺ T cells in cancer and cancer immunotherapy. British Journal of Cancer. 2021; 124: 359–367. https://doi.org/10.1038/s41416-020-01048-4.

[38] Denk D, Greten FR. Inflammation: the incubator of the tumor microenvironment. Trends in Cancer. 2022; 8: 901–914. https://doi.org/10.1016/j.trecan.2022.07.002.

[39] Tsan MF. Toll-like receptors, inflammation and cancer. Seminars in Cancer Biology. 2006; 16: 32–37. https://doi.org/10.1016/j.semcancer.2005.07.004.

[40] Chai EZP, Siveen KS, Shanmugam MK, Arfuso F, Sethi G. Analysis of the intricate relationship between chronic inflammation and cancer. The Biochemical Journal. 2015; 468: 1–15. https://doi.org/10.1042/BJ20141337.

[41] Ran S, Bhattarai N, Patel R, Volk-Draper L. Translational studies on inflammation. IntechOpen: United Kingdom. 2020.

[42] Candido J, Hagemann T. Cancer-related inflammation. Journal of Clinical Immunology. 2013; 33 Suppl 1: S79–S84. https://doi.org/10.1007/s10875-012-9847-0.

[43] Zinatizadeh MR, Schock B, Chalbatani GM, Zarandi PK, Jalali SA, Miri SR. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes & Diseases. 2020; 8: 287–297. https://doi.org/10.1016/j.gendis.2020.06.005.

[44] Sohrabi S, Alipour S, Ghahramanipour Z, Masoumi J, Baradaran B. STAT signaling pathways in immune cells and their associated mechanisms in cancer pathogenesis. Bioimpacts. 2025; 15: 30030.

[45] Sun Y, Lu Y, Saredy J, Wang X, Drummer Iv C, Shao Y, et al. ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes. Redox Biology. 2020; 37: 101696. https://doi.org/10.1016/j.redox.2020.101696.

[46] Yang Y, Bazhin AV, Werner J, Karakhanova S. Reactive oxygen species in the immune system. International Reviews of Immunology. 2013; 32: 249–270. https://doi.org/10.3109/08830185.2012.755176.

[47] Adwas AA, Elsayed A, Azab AE, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human body. Journal of Applied Biotechnology & Bioengineering. 2019; 6: 43–47.

[48] Zińczuk J, Maciejczyk M, Zaręba K, Pryczynicz A, Dymicka-Piekarska V, Kamińska J, et al. Pro-Oxidant Enzymes, Redox Balance and Oxidative Damage to Proteins, Lipids and DNA in Colorectal Cancer Tissue. Is Oxidative Stress Dependent on Tumour Budding and Inflammatory Infiltration? Cancers. 2020; 12: 1636. https://doi.org/10.3390/cancers12061636.

[49] Cadet J, Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harbor Perspectives in Biology. 2013; 5: a012559. https://doi.org/10.1101/cshperspect.a012559.

[50] Ivankova VS, Domina EA, Khrulenko TV, Makovetska LI, Hrinchenko OO, Baranovska LM. Effects of brachytherapy on cytogenetic parameters and oxidative status in peripheral blood lymphocytes of gynecologic cancer patients. Experimental Oncology. 2021; 43: 242–246. https://doi.org/10.32471/exp-oncology.2312-8852.vol-43-no-3.16514.

[51] Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative Stress in Cancer. Cancer Cell. 2020; 38: 167–197. https://doi.org/10.1016/j.ccell.2020.06.001.

[52] Weinberg F, Ramnath N, Nagrath D. Reactive Oxygen Species in the Tumor Microenvironment: An Overview. Cancers. 2019; 11: 1191. https://doi.org/10.3390/cancers11081191.

[53] Dahlgren C, Karlsson A. Respiratory burst in human neutrophils. Journal of Immunological Methods. 1999; 232: 3–14. https://doi.org/10.1016/s0022-1759(99)00146-5.

[54] Hawkins CL. The role of hypothiocyanous acid (HOSCN) in biological systems. Free Radical Research. 2009; 43: 1147–1158. https://doi.org/10.3109/10715760903214462.

[55] Peskin AV, Midwinter RG, Harwood DT, Winterbourn CC. Chlorine transfer between glycine, taurine, and histamine: reaction rates and impact on cellular reactivity. Free Radical Biology & Medicine. 2005; 38: 397–405. https://doi.org/10.1016/j.freeradbiomed.2004.11.006.

[56] Das AB, Seddon AR, O’Connor KM, Hampton MB. Regulation of the epigenetic landscape by immune cell oxidants. Free Radical Biology & Medicine. 2021; 170: 131–149. https://doi.org/10.1016/j.freeradbiomed.2020.12.453.

[57] Tan C, Aziz M, Wang P. The vitals of NETs. Journal of Leukocyte Biology. 2021; 110: 797–808. https://doi.org/10.1002/JLB.3RU0620-375R.

[58] Stoiber W, Obermayer A, Steinbacher P, Krautgartner WD. The Role of Reactive Oxygen Species (ROS) in the Formation of Extracellular Traps (ETs) in Humans. Biomolecules. 2015; 5: 702–723. https://doi.org/10.3390/biom5020702.

[59] Toraño EG, Petrus S, Fernandez AF, Fraga MF. Global DNA hypomethylation in cancer: review of validated methods and clinical significance. Clinical Chemistry and Laboratory Medicine. 2012; 50: 1733–1742. https://doi.org/10.1515/cclm-2011-0902.

[60] Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002; 21: 5427–5440. https://doi.org/10.1038/sj.onc.1205600.

[61] Cadet J, Delatour T, Douki T, Gasparutto D, Pouget JP, Ravanat JL, et al. Hydroxyl radicals and DNA base damage. Mutation Research. 1999; 424: 9–21. https://doi.org/10.1016/s0027-5107(99)00004-4.

[62] Chatgilialoglu C, Ferreri C, Krokidis MG, Masi A, Terzidis MA. On the relevance of hydroxyl radical to purine DNA damage. Free Radical Research. 2021; 55: 384–404. https://doi.org/10.1080/10715762.2021.1876855.

[63] Weitzman SA, Turk PW, Milkowski DH, Kozlowski K. Free radical adducts induce alterations in DNA cytosine methylation. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 1261–1264. https://doi.org/10.1073/pnas.91.4.1261.

[64] Bihaqi SW, Schumacher A, Maloney B, Lahiri DK, Zawia NH. Do epigenetic pathways initiate late onset Alzheimer disease (LOAD): towards a new paradigm. Current Alzheimer Research. 2012; 9: 574–588. https://doi.org/10.2174/156720512800617982.

[65] O’Connor KM, Das AB, Winterbourn CC, Hampton MB. Inhibition of DNA methylation in proliferating human lymphoma cells by immune cell oxidants. The Journal of Biological Chemistry. 2020; 295: 7839–7848. https://doi.org/10.1074/jbc.RA120.013092.

[66] Seddon AR, Das AB, Hampton MB, Stevens AJ. Site-specific decreases in DNA methylation in replicating cells following exposure to oxidative stress. Human Molecular Genetics. 2023; 32: 632–648. https://doi.org/10.1093/hmg/ddac232.

[67] Wentzensen IM, Mirabello L, Pfeiffer RM, Savage SA. The association of telomere length and cancer: a meta-analysis. Cancer Epidemiology, Biomarkers & Prevention: a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2011; 20: 1238–1250. https://doi.org/10.1158/1055-9965.EPI-11-0005.

[68] Seddon AR, Liau Y, Pace PE, Miller AL, Das AB, Kennedy MA, et al. Genome-wide impact of hydrogen peroxide on maintenance DNA methylation in replicating cells. Epigenetics & Chromatin. 2021; 14: 17. https://doi.org/10.1186/s13072-021-00388-6.

[69] Valinluck V, Liu P, Kang JI, Jr, Burdzy A, Sowers LC. 5-halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl-CpG-binding domain of methyl-CpG-binding protein 2 (MeCP2). Nucleic Acids Research. 2005; 33: 3057–3064. https://doi.org/10.1093/nar/gki612.

[70] Valinluck V, Sowers LC. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Research. 2007; 67: 946–950. https://doi.org/10.1158/0008-5472.CAN-06-3123.

[71] Lao VV, Herring JL, Kim CH, Darwanto A, Soto U, Sowers LC. Incorporation of 5-chlorocytosine into mammalian DNA results in heritable gene silencing and altered cytosine methylation patterns. Carcinogenesis. 2009; 30: 886–893. https://doi.org/10.1093/carcin/bgp060.

[72] Niu Y, DesMarais TL, Tong Z, Yao Y, Costa M. Oxidative stress alters global histone modification and DNA methylation. Free Radical Biology & Medicine. 2015; 82: 22–28. https://doi.org/10.1016/j.freeradbiomed.2015.01.028.

[73] Zhang YW, Wang Z, Xie W, Cai Y, Xia L, Easwaran H, et al. Acetylation Enhances TET2 Function in Protecting against Abnormal DNA Methylation during Oxidative Stress. Molecular Cell. 2017; 65: 323–335. https://doi.org/10.1016/j.molcel.2016.12.013.

[74] Wang Q, Wang W, Zhang A. TET-mediated DNA demethylation plays an important role in arsenic-induced HBE cells oxidative stress via regulating promoter methylation of OGG1 and GSTP1. Toxicology in Vitro: an International Journal Published in Association with BIBRA. 2021; 72: 105075. https://doi.org/10.1016/j.tiv.2020.105075.

[75] Lu X, Zhao BS, He C. TET family proteins: oxidation activity, interacting molecules, and functions in diseases. Chemical Reviews. 2015; 115: 2225–2239. https://doi.org/10.1021/cr500470n.

[76] Kirkegård J, Mortensen FV, Cronin-Fenton D. Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. The American Journal of Gastroenterology. 2017; 112: 1366–1372. https://doi.org/10.1038/ajg.2017.218.

[77] Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Practice & Research. Clinical Gastroenterology. 2010; 24: 349–358. https://doi.org/10.1016/j.bpg.2010.02.007.

[78] Gandhi S, de la Fuente J, Murad MH, Majumder S. Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis. Clinical and Translational Gastroenterology. 2022; 13: e00463. https://doi.org/10.14309/ctg.0000000000000463.

[79] Waldum H, Fossmark R. Gastritis, Gastric Polyps and Gastric Cancer. International Journal of Molecular Sciences. 2021; 22: 6548. https://doi.org/10.3390/ijms22126548.

[80] Sugimoto M, Ban H, Ichikawa H, Sahara S, Otsuka T, Inatomi O, et al. Efficacy of the Kyoto Classification of Gastritis in Identifying Patients at High Risk for Gastric Cancer. Internal Medicine (Tokyo, Japan). 2017; 56: 579–586. https://doi.org/10.2169/internalmedicine.56.7775.

[81] Niu Q, Zhu J, Yu X, Feng T, Ji H, Li Y, et al. Immune Response in H. pylori-Associated Gastritis and Gastric Cancer. Gastroenterology Research and Practice. 2020; 2020: 9342563. https://doi.org/10.1155/2020/9342563.

[82] Mattar MC, Lough D, Pishvaian MJ, Charabaty A. Current management of inflammatory bowel disease and colorectal cancer. Gastrointestinal Cancer Research: GCR. 2011; 4: 53–61.

[83] Stidham RW, Higgins PDR. Colorectal Cancer in Inflammatory Bowel Disease. Clinics in Colon and Rectal Surgery. 2018; 31: 168–178. https://doi.org/10.1055/s-0037-1602237.

[84] Shah SC, Itzkowitz SH. Colorectal Cancer in Inflammatory Bowel Disease: Mechanisms and Management. Gastroenterology. 2022; 162: 715–730.e713. https://doi.org/10.1053/j.gastro.2021.10.035.

[85] Keller J, Chiou HY, Lin HC. Increased risk of bladder cancer following diagnosis with bladder pain syndrome/interstitial cystitis. Neurourology and Urodynamics. 2013; 32: 58–62. https://doi.org/10.1002/nau.22283.

[86] Vermeulen SH, Hanum N, Grotenhuis AJ, Castaño-Vinyals G, van der Heijden AG, Aben KK, et al. Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study. British Journal of Cancer. 2015; 112: 594–600. https://doi.org/10.1038/bjc.2014.601.

[87] Fitzpatrick SG, Katz J. The association between periodontal disease and cancer: a review of the literature. Journal of Dentistry. 2010; 38: 83–95. https://doi.org/10.1016/j.jdent.2009.10.007.

[88] Farhad SZ, Karbalaeihasanesfahani A, Dadgar E, Nasiri K, Esfahaniani M, Nabi Afjadi M. The role of periodontitis in cancer development, with a focus on oral cancers. Molecular Biology Reports. 2024; 51: 814. https://doi.org/10.1007/s11033-024-09737-6.

[89] Keikha M, Esfahani BN. The Relationship between Tuberculosis and Lung Cancer. Advanced Biomedical Research. 2018; 7: 58. https://doi.org/10.4103/abr.abr_182_17.

[90] Ang L, Ghosh P, Seow WJ. Association between previous lung diseases and lung cancer risk: a systematic review and meta-analysis. Carcinogenesis. 2021; 42: 1461–1474. https://doi.org/10.1093/carcin/bgab082.

[91] Spechler SJ. Barrett esophagus and risk of esophageal cancer: a clinical review. JAMA. 2013; 310: 627–636. https://doi.org/10.1001/jama.2013.226450.

[92] Thrift AP. Global burden and epidemiology of Barrett oesophagus and oesophageal cancer. Nature Reviews. Gastroenterology & Hepatology. 2021; 18: 432–443. https://doi.org/10.1038/s41575-021-00419-3.

[93] Jain S, Dhingra S. Pathology of esophageal cancer and Barrett’s esophagus. Annals of Cardiothoracic Surgery. 2017; 6: 99–109. https://doi.org/10.21037/acs.2017.03.06.

[94] Kanavy HE, Gerstenblith MR. Ultraviolet radiation and melanoma. Seminars in Cutaneous Medicine and Surgery. 2011; 30: 222–228. https://doi.org/10.1016/j.sder.2011.08.003.

[95] Neagu M, Constantin C, Caruntu C, Dumitru C, Surcel M, Zurac S. Inflammation: A key process in skin tumorigenesis. Oncology Letters. 2019; 17: 4068–4084. https://doi.org/10.3892/ol.2018.9735.

[96] Tang L, Wang K. Chronic Inflammation in Skin Malignancies. Journal of Molecular Signaling. 2016; 11: 2. https://doi.org/10.5334/1750-2187-11-2.

[97] Vockerodt M, Yap LF, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K, et al. The Epstein-Barr virus and the pathogenesis of lymphoma. The Journal of Pathology. 2015; 235: 312–322. https://doi.org/10.1002/path.4459.

[98] Shannon-Lowe C, Rickinson AB, Bell AI. Epstein-Barr virus-associated lymphomas. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2017; 372: 20160271. https://doi.org/10.1098/rstb.2016.0271.

[99] Sausen DG, Basith A, Muqeemuddin S. EBV and Lymphomagenesis. Cancers. 2023; 15: 2133. https://doi.org/10.3390/cancers15072133.

[100] D’souza S, Lau KC, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World Journal of Gastroenterology. 2020; 26: 5759–5783. https://doi.org/10.3748/wjg.v26.i38.5759.

[101] Zhang X, Guan L, Tian H, Zeng Z, Chen J, Huang D, et al. Risk Factors and Prevention of Viral Hepatitis-Related Hepatocellular Carcinoma. Frontiers in Oncology. 2021; 11: 686962. https://doi.org/10.3389/fonc.2021.686962.

[102] Piao J, Lee EJ, Lee M. Association between pelvic inflammatory disease and risk of ovarian cancer: An updated meta-analysis. Gynecologic Oncology. 2020; 157: 542–548. https://doi.org/10.1016/j.ygyno.2020.02.002.

[103] Jonsson S, Jonsson H, Lundin E, Häggström C, Idahl A. Pelvic inflammatory disease and risk of epithelial ovarian cancer: a national population-based case-control study in Sweden. American Journal of Obstetrics and Gynecology. 2024; 230: 75.e1–75.e15. https://doi.org/10.1016/j.ajog.2023.09.094.

[104] Roa JC, García P, Kapoor VK, Maithel SK, Javle M, Koshiol J. Gallbladder cancer. Nature Reviews. Disease Primers. 2022; 8: 69. https://doi.org/10.1038/s41572-022-00398-y.

[105] Kucuk S, Mızrak S. Diagnostic Value of Inflammatory Factors in Patients with Gallbladder Cancer, Dysplasia, and Cholecystitis. Cancer Control: Journal of the Moffitt Cancer Center. 2021; 28: 10732748211033746. https://doi.org/10.1177/10732748211033746.

[106] Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet (London, England). 2014; 383: 2168–2179. https://doi.org/10.1016/S0140-6736(13)61903-0.

[107] González MI, Vannan DT, Eksteen B, Flores-Sotelo I, Reyes JL. Mast Cells in Immune-Mediated Cholangitis and Cholangiocarcinoma. Cells. 2022; 11: 375. https://doi.org/10.3390/cells11030375.

[108] Worley MJ, Welch WR, Berkowitz RS, Ng SW. Endometriosis-associated ovarian cancer: a review of pathogenesis. International Journal of Molecular Sciences. 2013; 14: 5367–5379. https://doi.org/10.3390/ijms14035367.

[109] Barnard ME, Farland LV, Yan B, Wang J, Trabert B, Doherty JA, et al. Endometriosis Typology and Ovarian Cancer Risk. JAMA. 2024; 332: 482–489. https://doi.org/10.1001/jama.2024.9210.

[110] Yu HC, Lin CY, Chang WC, Shen BJ, Chang WP, Chuang CM, et al. Increased association between endometriosis and endometrial cancer: a nationwide population-based retrospective cohort study. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society. 2015; 25: 447–452. https://doi.org/10.1097/IGC.0000000000000384.

[111] Kvaskoff M, Mahamat-Saleh Y, Farland LV, Shigesi N, Terry KL, Harris HR, et al. Endometriosis and cancer: a systematic review and meta-analysis. Human Reproduction Update. 2021; 27: 393–420. https://doi.org/10.1093/humupd/dmaa045.

[112] Paparodis R, Imam S, Todorova-Koteva K, Staii A, Jaume JC. Hashimoto’s thyroiditis pathology and risk for thyroid cancer. Thyroid: Official Journal of the American Thyroid Association. 2014; 24: 1107–1114. https://doi.org/10.1089/thy.2013.0588.

[113] Xu S, Huang H, Qian J, Liu Y, Huang Y, Wang X, et al. Prevalence of Hashimoto Thyroiditis in Adults With Papillary Thyroid Cancer and Its Association With Cancer Recurrence and Outcomes. JAMA Network Open. 2021; 4: e2118526. https://doi.org/10.1001/jamanetworkopen.2021.18526.

[114] Shen K, Xu G, Wu Q, Zhou D, Li J. Risk of multiple myeloma in rheumatoid arthritis: a meta-analysis of case-control and cohort studies. PloS One. 2014; 9: e91461. https://doi.org/10.1371/journal.pone.0091461.

[115] Wang G, Zhuo N, Tang M, Xue L, Liu Z. Seronegative rheumatoid arthritis as the first manifestation of multiple myeloma-associated amyloid arthropathy. Archives of Medical Science: AMS. 2023; 19: 539–541. https://doi.org/10.5114/aoms/161285.

[116] Wang J, Gao W, Yu H, Xu Y, Bai C, Cong Q, et al. Research Progress on the Role of Epigenetic Methylation Modification in Hepatocellular Carcinoma. Journal of Hepatocellular Carcinoma. 2024; 11: 1143–1156. https://doi.org/10.2147/JHC.S458734.

[117] Aregay A, Owusu Sekyere S, Deterding K, Port K, Dietz J, Berkowski C, et al. Elimination of hepatitis C virus has limited impact on the functional and mitochondrial impairment of HCV-specific CD8+ T cell responses. Journal of Hepatology. 2019; 71: 889–899. https://doi.org/10.1016/j.jhep.2019.06.025.

[118] Gong G, Waris G, Tanveer R, Siddiqui A. Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B. Proceedings of the National Academy of Sciences of the United States of America. 2001; 98: 9599–9604. https://doi.org/10.1073/pnas.171311298.

[119] McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology (Baltimore, Md.). 2021; 73 Suppl 1: 4–13. https://doi.org/10.1002/hep.31288.

[120] Mitchell JK, Lemon SM, McGivern DR. How do persistent infections with hepatitis C virus cause liver cancer? Current Opinion in Virology. 2015; 14: 101–108. https://doi.org/10.1016/j.coviro.2015.09.003.

[121] Wong SHM, Fang CM, Chuah LH, Leong CO, Ngai SC. E-cadherin: Its dysregulation in carcinogenesis and clinical implications. Critical Reviews in Oncology/hematology. 2018; 121: 11–22. https://doi.org/10.1016/j.critrevonc.2017.11.010.

[122] Na TY, Schecterson L, Mendonsa AM, Gumbiner BM. The functional activity of E-cadherin controls tumor cell metastasis at multiple steps. Proceedings of the National Academy of Sciences of the United States of America. 2020; 117: 5931–5937. https://doi.org/10.1073/pnas.1918167117.

[123] Matsumura T, Makino R, Mitamura K. Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. 2001; 7: 594–599.

[124] Nakagawa H, Hikiba Y, Hirata Y, Font-Burgada J, Sakamoto K, Hayakawa Y, et al. Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111: 1090–1095. https://doi.org/10.1073/pnas.1322731111.

[125] Nishida N, Arizumi T, Takita M, Kitai S, Yada N, Hagiwara S, et al. Reactive oxygen species induce epigenetic instability through the formation of 8-hydroxydeoxyguanosine in human hepatocarcinogenesis. Digestive Diseases (Basel, Switzerland). 2013; 31: 459–466. https://doi.org/10.1159/000355245.

[126] Salvatori S, Marafini I, Laudisi F, Monteleone G, Stolfi C. Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms. International Journal of Molecular Sciences. 2023; 24: 2895. https://doi.org/10.3390/ijms24032895.

[127] Yousefi B, Mohammadlou M, Abdollahi M, Salek Farrokhi A, Karbalaei M, Keikha M, et al. Epigenetic changes in gastric cancer induction by Helicobacter pylori. Journal of Cellular Physiology. 2019; 234: 21770–21784. https://doi.org/10.1002/jcp.28925.

[128] Capparelli R, Iannelli D. Epigenetics and Helicobacter pylori. International Journal of Molecular Sciences. 2022; 23: 1759. https://doi.org/10.3390/ijms23031759.

[129] Yang H, Wei B, Hu B. Chronic inflammation and long-lasting changes in the gastric mucosa after Helicobacter pylori infection involved in gastric cancer. Inflammation Research. 2021; 70: 1015–1026. https://doi.org/10.1007/s00011-021-01501-x.

[130] Niwa T, Toyoda T, Tsukamoto T, Mori A, Tatematsu M, Ushijima T. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer Prevention Research (Philadelphia, Pa.). 2013; 6: 263–270. https://doi.org/10.1158/1940-6207.CAPR-12-0369.

[131] Leung WK, Man EPS, Yu J, Go MYY, To KF, Yamaoka Y, et al. Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. 2006; 12: 3216–3221. https://doi.org/10.1158/1078-0432.CCR-05-2442.

[132] Schneider BG, Piazuelo MB, Sicinschi LA, Mera R, Peng DF, Roa JC, et al. Virulence of infecting Helicobacter pylori strains and intensity of mononuclear cell infiltration are associated with levels of DNA hypermethylation in gastric mucosae. Epigenetics. 2013; 8: 1153–1161. https://doi.org/10.4161/epi.26072.

[133] Nakajima T, Enomoto S, Yamashita S, Ando T, Nakanishi Y, Nakazawa K, et al. Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication. Journal of Gastroenterology. 2010; 45: 37–44. https://doi.org/10.1007/s00535-009-0142-7.

[134] Katayama Y, Takahashi M, Kuwayama H. Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochemical and Biophysical Research Communications. 2009; 388: 496–500. https://doi.org/10.1016/j.bbrc.2009.08.003.

[135] Chan AOO, Lam SK, Wong BCY, Wong WM, Yuen MF, Yeung YH, et al. Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut. 2003; 52: 502–506. https://doi.org/10.1136/gut.52.4.502.

[136] Miao R, Guo X, Zhi Q, Shi Y, Li L, Mao X, et al. VEZT, a novel putative tumor suppressor, suppresses the growth and tumorigenicity of gastric cancer. PloS One. 2013; 8: e74409. https://doi.org/10.1371/journal.pone.0074409.

[137] Wang Y, Huang LH, Xu CX, Xiao J, Zhou L, Cao D, et al. Connexin 32 and 43 promoter methylation in Helicobacter pylori-associated gastric tumorigenesis. World Journal of Gastroenterology. 2014; 20: 11770–11779. https://doi.org/10.3748/wjg.v20.i33.11770.

[138] Perri F, Cotugno R, Piepoli A, Merla A, Quitadamo M, Gentile A, et al. Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication. The American Journal of Gastroenterology. 2007; 102: 1361–1371. https://doi.org/10.1111/j.1572-0241.2007.01284.x.

[139] Alvarez MC, Santos JC, Maniezzo N, Ladeira MS, da Silva ALC, Scaletsky ICA, et al. MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults. World Journal of Gastroenterology. 2013; 19: 3043–3051. https://doi.org/10.3748/wjg.v19.i20.3043.

[140] Peterson AJ, Menheniott TR, O’Connor L, Walduck AK, Fox JG, Kawakami K, et al. Helicobacter pylori infection promotes methylation and silencing of trefoil factor 2, leading to gastric tumor development in mice and humans. Gastroenterology. 2010; 139: 2005–2017. https://doi.org/10.1053/j.gastro.2010.08.043.

[141] Lucafò M, Curci D, Franzin M, Decorti G, Stocco G. Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention. Frontiers in Pharmacology. 2021; 12: 772101. https://doi.org/10.3389/fphar.2021.772101.

[142] Hartnett L, Egan LJ. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis. 2012; 33: 723–731. https://doi.org/10.1093/carcin/bgs006.

[143] Maiuri AR, O’Hagan HM. Interplay Between Inflammation and Epigenetic Changes in Cancer. Progress in Molecular Biology and Translational Science. 2016; 144: 69–117. https://doi.org/10.1016/bs.pmbts.2016.09.002.

[144] Pereira C, Grácio D, Teixeira JP, Magro F. Oxidative Stress and DNA Damage: Implications in Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2015; 21: 2403–2417. https://doi.org/10.1097/MIB.0000000000000506.

[145] Hansberry DR, Shah K, Agarwal P, Agarwal N. Fecal Myeloperoxidase as a Biomarker for Inflammatory Bowel Disease. Cureus. 2017; 9: e1004. https://doi.org/10.7759/cureus.1004.

[146] Swaminathan A, Borichevsky GM, Frampton CM, Day AS, Hampton MB, Kettle AJ, et al. Comparison of Fecal Calprotectin and Myeloperoxidase in Predicting Outcomes in Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 2024; izae032. https://doi.org/10.1093/ibd/izae032.

[147] Yi JM, Kim TO. Epigenetic alterations in inflammatory bowel disease and cancer. Intestinal Research. 2015; 13: 112–121. https://doi.org/10.5217/ir.2015.13.2.112.

[148] Jung G, Hernández-Illán E, Lozano JJ, Sidorova J, Muñoz J, Okada Y, et al. Epigenome-Wide DNA Methylation Profiling of Normal Mucosa Reveals HLA-F Hypermethylation as a Biomarker Candidate for Serrated Polyposis Syndrome. The Journal of Molecular Diagnostics: JMD. 2022; 24: 674–686. https://doi.org/10.1016/j.jmoldx.2022.03.010.

[149] Kang KA, Zhang R, Kim GY, Bae SC, Hyun JW. Epigenetic changes induced by oxidative stress in colorectal cancer cells: methylation of tumor suppressor RUNX3. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine. 2012; 33: 403–412. https://doi.org/10.1007/s13277-012-0322-6.

[150] O’Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell. 2011; 20: 606–619. https://doi.org/10.1016/j.ccr.2011.09.012.

[151] de Oliveira NFP, de Souza BF, de Castro Coêlho M. UV Radiation and Its Relation to DNA Methylation in Epidermal Cells: A Review. Epigenomes. 2020; 4: 23. https://doi.org/10.3390/epigenomes4040023.

[152] Maru GB, Gandhi K, Ramchandani A, Kumar G. The role of inflammation in skin cancer. Advances in Experimental Medicine and Biology. 2014; 816: 437–469. https://doi.org/10.1007/978-3-0348-0837-8_17.

[153] Yang Y, Wu R, Sargsyan D, Yin R, Kuo HC, Yang I, et al. UVB drives different stages of epigenome alterations during progression of skin cancer. Cancer Letters. 2019; 449: 20–30. https://doi.org/10.1016/j.canlet.2019.02.010.

[154] Li Y, Sawalha AH, Lu Q. Aberrant DNA methylation in skin diseases. Journal of Dermatological Science. 2009; 54: 143–149. https://doi.org/10.1016/j.jdermsci.2009.01.009.

[155] De Smet C, Loriot A, Boon T. Promoter-dependent mechanism leading to selective hypomethylation within the 5’ region of gene MAGE-A1 in tumor cells. Molecular and Cellular Biology. 2004; 24: 4781–4790. https://doi.org/10.1128/MCB.24.11.4781-4790.2004.

[156] Pergoli L, Favero C, Pfeiffer RM, Tarantini L, Calista D, Cavalleri T, et al. Blood DNA methylation, nevi number, and the risk of melanoma. Melanoma Research. 2014; 24: 480–487. https://doi.org/10.1097/CMR.0000000000000112.

[157] Yang ES, Hwang JS, Choi HC, Hong RH, Kang SM. The effect of genistein on melanin synthesis and in vivo whitening. Korean Journal of Microbiology and Biotechnology. 2008; 36: 72–81.

[158] Shiau RJ, Wu JY, Chiou SJ, Wen YD. Effects of curcumin on nitrosyl-iron complex-mediated DNA cleavage and cytotoxicity. Planta Medica. 2012; 78: 1342–1350. https://doi.org/10.1055/s-0032-1315020.

[159] Li Y, Saldanha SN, Tollefsbol TO. Impact of epigenetic dietary compounds on transgenerational prevention of human diseases. The AAPS Journal. 2014; 16: 27–36. https://doi.org/10.1208/s12248-013-9538-7.

[160] Molognoni F, de Melo FHM, da Silva CT, Jasiulionis MG. Ras and Rac1, frequently mutated in melanomas, are activated by superoxide anion, modulate Dnmt1 level and are causally related to melanocyte malignant transformation. PloS One. 2013; 8: e81937. https://doi.org/10.1371/journal.pone.0081937.

[161] Burke KE, Wei H. Synergistic damage by UVA radiation and pollutants. Toxicology and Industrial Health. 2009; 25: 219–224. https://doi.org/10.1177/0748233709106067.

Funding

Canterbury Medical Research Foundation and the Wellington Research Foundation: Research for Life