Epigenetic alterations, such as abnormal DNA-methylation patterns, are associated with many human tumour types. New techniques have been developed to perform genome-wide screening for alterations in ...DNA-methylation patterns, not only to identify tumour-suppressor genes, but also to find patterns that can be used in diagnosis and prognosis. However, interpretation of differential methylation has proven difficult because the significance of methylation alterations depends on the genomic region, and functions of CpG islands at specific sites have not been fully clarified. What techniques can be used to identify new tumour suppressors and diagnostic markers?
Cancers develop due to the accumulation of genetic and epigenetic alterations. Genetic alterations are induced by aging, mutagenic chemicals, ultraviolet light, and other factors; whereas, epigenetic ...alterations are mainly by aging and chronic inflammation. The accumulation and patterns of alterations in normal cells reflect our past exposure levels and life history. Most accumulated alterations are considered as passengers, but their accumulation is correlated with cancer drivers. This has been shown for aberrant DNA methylation but has only been speculated for genetic alterations. However, recent technological advancements have enabled measurement of rare point mutations, and studies have shown that their accumulation levels are indeed correlated with cancer risk. When the accumulation levels of aberrant DNA methylation and point mutations are combined, risk prediction becomes even more accurate. When high levels of alterations accumulate, the tissue has a high risk of developing cancer or even multiple cancers and is considered as a "cancerization field", with or without expansion of physiological patches of clonal cells. In this review, we describe the formation of a cancerization field and how we can apply its detection in precision cancer risk diagnosis.
Chronic inflammation, regardless of infectious agents, plays important roles in the development of various cancers, particularly in digestive organs, including Helicobacter pylori –associated gastric ...cancer, hepatitis C virus–positive hepatocellular carcinoma, and colitis-associated colon cancers. Cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations of various proto-oncogenes and tumor-suppressor genes. During chronic inflammation, infectious agents such as H pylori and hepatitis C virus as well as intrinsic mediators of inflammatory responses, including proinflammatory cytokines and reactive oxygen and nitrogen species, can induce genetic and epigenetic changes, including point mutations, deletions, duplications, recombinations, and methylation of various tumor-related genes through various mechanisms. Furthermore, inflammation also modulates the expressions of microRNAs that influence the production of several tumor-related messenger RNAs or proteins. These molecular events induced by chronic inflammation work in concert to alter important pathways involved in normal cellular function, and hence accelerate inflammation-associated cancer development. Among these, recent studies highlighted an important role of activation-induced cytidine deaminase, a nucleotide-editing enzyme essential for somatic hypermutation and class-switch recombination of the immunoglobulin gene, as a genomic modulator in inflammation-associated cancer development.
Gastric cancer is a deadly malignancy afflicting close to a million people worldwide. Patient survival is poor and largely due to late diagnosis and suboptimal therapies. Disease heterogeneity is a ...substantial obstacle, underscoring the need for precision treatment strategies. Studies have identified different subgroups of gastric cancer displaying not just genetic, but also distinct epigenetic hallmarks. Accumulating evidence suggests that epigenetic abnormalities in gastric cancer are not mere bystander events, but rather promote carcinogenesis through active mechanisms. Epigenetic aberrations, induced by pathogens such as Helicobacter pylori, are an early component of gastric carcinogenesis, probably preceding genetic abnormalities. This Review summarizes our current understanding of the gastric cancer epigenome, highlighting key advances in recent years in both tumours and pre-malignant lesions, made possible through targeted and genome-wide technologies. We focus on studies related to DNA methylation and histone modifications, linking these findings to potential therapeutic opportunities. Lessons learned from the gastric cancer epigenome might also prove relevant for other gastrointestinal cancers.
Viral and bacterial infections are involved in the development of human cancers, such as liver, nasopharyngeal, cervical, head and neck, and gastric cancers. Aberrant DNA methylation is frequently ...present in these cancers, and some of the aberrantly methylated genes are causally involved in cancer development and progression. Notably, aberrant DNA methylation can be present even in non-cancerous or precancerous tissues, and its levels correlate with the risk of cancer development, producing a so-called 'epigenetic field for cancerization'. Mechanistically, most viral or bacterial infections induce DNA methylation indirectly via chronic inflammation, but recent studies have indicated that some viruses have direct effects on the epigenetic machinery of host cells. From a translational viewpoint, a recent multicenter prospective cohort study demonstrated that assessment of the extent of alterations in DNA methylation in non-cancerous tissues can be used to predict cancer risk. Furthermore, suppression of aberrant DNA methylation was shown to be a useful strategy for cancer prevention in an animal model. Here, we review the involvement of aberrant DNA methylation in various types of infection-associated cancers, along with individual induction mechanisms, and we discuss the application of these findings for cancer prevention, diagnosis, and therapy.
Infection-associated cancers account for a large proportion of human cancers, and gastric cancer, the vast majority of which is associated with Helicobacter pylori infection, is a typical example of ...such cancers. Epigenetic alterations are known to occur frequently in gastric cancers, and H. pylori infection has now been shown to induce aberrant DNA methylation in gastric mucosae. Accumulation of aberrant methylation in gastric mucosae produces a field for cancerization, and methylation levels correlate with gastric cancer risk. H. pylori infection induces methylation of specific genes, and such specificity is determined by the epigenetic status in normal cells, including the presence of H3K27me3 and RNA polymerase II (active or stalled). Specific types of inflammation, such as that induced by H. pylori infection, are important for methylation induction, and infiltration of monocytes appears to be involved. The presence of an epigenetic field defect is not limited to gastric cancers and is observed in various types of cancers. It provides translational opportunities for cancer risk diagnosis incorporating life history, assessment of past exposure to carcinogenic factors, and cancer prevention.
Mapping genomic and epigenomic evolution in cancer ecosystems Ushijima, Toshikazu; Clark, Susan J; Tan, Patrick
Science (American Association for the Advancement of Science),
2021-Sep-24, 2021-09-24, 20210924, Letnik:
373, Številka:
6562
Journal Article
Recenzirano
Cancer is a major cause of global mortality underpinned by genomic and epigenomic derangements. Here, we highlight the importance of multimodal data integration in understanding the molecular ...evolution of malignant cell states across the cancer life cycle. The widespread presence of driver mutations and epigenetic alterations in normal-appearing tissues is prompting a reassessment of how cancer initiation is defined. In later-stage cancers, studying the roles of clonal selection, epigenomic adaptation, and persister cells in metastasis and therapy resistance is an emerging field. Finally, the importance of tumor ecosystems in driving cancer development is being unraveled by single-cell and spatial technologies at unprecedented resolution. Improving cancer risk assessment and accelerating therapeutic discovery for patients will require robust, comprehensive, and integrated temporal, spatial, and multilevel tumor atlases across the cancer life cycle.
•Aberrant epigenetic alterations are involved in cancer development and progression.•Drugs targeting epigenetic regulators and readers have been developed.•DNA methylation can be used as a biomarker ...for cancer diagnosis.•The overview and trends of cancer epigenetics are summarized.
Epigenetics now refers to the study or research field related to DNA methylation and histone modifications. Historically, global DNA hypomethylation was first revealed in 1983, and, after a decade, silencing of a tumor suppressor gene by regional DNA hypermethylation was reported. After the proposal of the histone code in the 2000s, alterations of histone methylation were also identified in cancers. Now, it is established that aberrant epigenetic alterations are involved in cancer development and progression, along with mutations and chromosomal losses. Recent cancer genome analyses have revealed a large number of mutations of epigenetic modifiers, supporting their important roles in cancer pathogenesis. Taking advantage of the reversibility of epigenetic alterations, drugs targeting epigenetic regulators and readers have been developed for restoration of normal pattern of the epigenome, and some have already demonstrated clinical benefits. In addition, DNA methylation of specific marker genes can be used as a biomarker for cancer diagnosis, including risk diagnosis, detection of cancers, and pathophysiological diagnosis. In this paper, we will summarize the major concepts of cancer epigenetics, placing emphasis on history.
Multiple pathogenic mechanisms by which
Helicobacter pylori
infection induces gastric cancer have been established in the last two decades. In particular, aberrant DNA methylation is induced in ...multiple driver genes, which inactivates them. Methylation profiles in gastric cancer are associated with specific subtypes, such as microsatellite instability. Recent comprehensive and integrated analyses showed that many cancer-related pathways are more frequently altered by aberrant DNA methylation than by mutations. Aberrant DNA methylation can even be present in noncancerous gastric mucosae, producing an “epigenetic field for cancerization.” Mechanistically,
H. pylori
-induced chronic inflammation, but not
H. pylori
itself, plays a direct role in the induction of aberrant DNA methylation. The expression of three inflammation-related genes,
Il1b, Nos2, and Tnf
, is highly associated with the induction of aberrant DNA methylation. Importantly, the degree of accumulated aberrant DNA methylation is strongly correlated with gastric cancer risk. A recent multicenter prospective cohort study demonstrated the utility of epigenetic cancer risk diagnosis for metachronous gastric cancer. Suppression of aberrant DNA methylation by a demethylating agent was shown to inhibit gastric cancer development in an animal model. Induction of aberrant DNA methylation is the major pathway by which
H. pylori
infection induces gastric cancer, and this can be utilized for translational opportunities.
Background
Gastric cancer is heavily influenced by aberrant DNA methylation that alters multiple cancer-related pathways, and may respond to DNA demethylating agents, such as 5-aza-2′-deoxycytidine ...(5-aza-dC). Here, we aimed to analyze whether 5-aza-dC can sensitize gastric cancer cells to clinically used cytotoxic drugs.
Methods
Ten gastric cancer cell lines were treated with 5-aza-dC for 72 h and their growth was analyzed by conducting WST assay. In vivo effect of the drugs was analyzed using xenografts of OCUM-2 M/SN38 cells. Genome-wide expression and DNA methylation analyses were conducted using microarrays, and biological functions were identified through ingenuity pathway analysis.
Results
The cell lines most resistant to SN38 (an active metabolite of irinotecan), CDDP, PTX, and 5-FU, were identified. 5-Aza-dC pre-treatment of the resistant cell lines decreased the IC
50
values for SN38 (TMK1, 226.4 nM to 32.91 nM; 44As3, 128.2 nM to 19.32 nM; OCUM2 M/SN38, 74.43 nM to 16.47 nM) and CDDP (TMK1, 5.05 µM to 2.26 µM; OCUM2 M, 10.79 µM to 2.77 µM), but not PTX and 5-FU. The reactivation of apoptosis-related genes, such as
RUNX3
,
PYCARD, TNF, FAS
, and
FASLG,
was induced by pre-treatment with 5-aza-dC, and the DNA demethylation of promoter CpG islands of
RUNX3
and
PYCARD
was confirmed. In a xenograft model with OCUM2 M/SN38, treatment with 5-aza-dC before irinotecan showed markedly enhanced tumor suppression.
Conclusion
Epigenetic priming with 5-aza-dC can improve the sensitivity of gastric cancer cells to SN38 and CDDP.
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