Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma

Okabe, Atsushi; Huang, Kie Kyon; Matsusaka, Keisuke; Fukuyo, Masaki; Xing, Manjie; Ong, Xuewen; Hoshii, Takayuki; Usui, Genki; Seki, Masanori; Mano, Yasunobu; Rahmutulla, Bahityar; Kanda, Teru; Suzuki, Takayoshi; Rha, Sun Young; Ushiku, Tetsuo; Fukayama, Masashi; Tan, Patrick; Kaneda, Atsushi

doi:10.1038/s41588-020-0665-7

Cited by 79 publications

(87 citation statements)

References 47 publications

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“…A recent study suggested that enhancer activation through ATF3 might be involved in carcinogenesis [32]. Our latest study has revealed that interaction of episomal EBV genome may directly rewire the host chromatin structure to aberrantly activate proto-oncogenes and promote gastric carcinogenesis [17]. In the study, Hi-C analysis showed the specific interaction between viral and human genomes in EBV(+) GC cell lines and primary tissues of human EBV(+) GC.…”

Section: Epigenetic Aberrant In Gastric Cancermentioning

confidence: 99%

“…This is because EBV genome preferentially interacts with H3K9me3(+) heterochromatins and converts the regions from repressive H3K9me3(+) state to active H3K4me1(+)/H3K27ac(+) state. Enhancers silenced in the heterochromatin are thus aberrantly activated in EBVIRs and can upregulate nearby GC-related genes such as TGFBR2 and MZT1 [17].…”

Section: Epigenetic Aberrant In Gastric Cancermentioning

confidence: 99%

“…E-HME is observed in EBV-positive GC; frequently have CDKN2A methylation, PIK3CA mutations, and PD-L1/2 overexpression; and generally lack TP53 mutations. Proto-oncogenes such as MZT1 are activated by “enhancer infestation” [17]. HME often has MLH methylation and abundant gene mutations, including PIK3CA, ARID1A , and RTK.…”

Section: Genetic Aberrations In Gastric Cancermentioning

confidence: 99%

“…Genomic rearrangements are involved in “enhancer hijacking,” promoting the expression of CCNE1 and IGF2 . Our latest study of EBV(+) GC has shown that episomal viral genomes interact with human genome and rewire the human chromatin structure [17]. Silenced enhancers are aberrantly activated by the chromatin rewiring (named “enhancer infestation”) and can upregulate neighboring proto-oncogenes to promote gastric carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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DNA Methylation and Genetic Aberrations in Gastric Cancer

et al. 2020

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Background: Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. GC is a pathologically and molecularly heterogeneous disease. DNA hypermethylation in promoter CpG islands causes silencing of tumor-suppressor genes and thus contributes to gastric carcinogenesis. In addition, various molecular aberrations, including aberrant chromatin structures, gene mutations, structural variants, and somatic copy number alterations, are involved in gastric carcinogenesis. Summary: Comprehensive DNA methylation analyses revealed multiple DNA methylation patterns in GCs and classified GC into distinct molecular subgroups: extremely high-methylation epigenotype uniquely observed in GC associated with Epstein-Barr virus (EBV), high-methylation epigenotype associated with microsatellite instability (MSI), and low-methylation epigenotype. In The Cancer Genome Atlas classification, EBV and MSI are extracted as independent subgroups of GC, whereas the remaining GCs are categorized into genomically stable (GS) and chromosomal instability (CIN) subgroups. EBV-positive GC, exhibiting the most extreme DNA hypermethylation in the whole human malignancies, frequently shows CDKN2A silencing, PIK3CA mutations, PD-L1/2 overexpression, and lack of TP53 mutations. MSI, exhibiting high DNA methylation, often has MLH1 silencing and abundant gene mutations. GS is generally a diffuse-type GC and frequently shows CDH1/RHOA mutations or CLDN18–ARHGAP fusion. CIN is generally an intestinal-type GC and frequently has TP53 mutations and genomic amplification of receptor tyrosine kinases. Key Messages: The frequency and targets of genetic aberrations vary depending on the epigenotype. Aberrations in the genome and epigenome are expected to synergistically interact and contribute to gastric carcinogenesis and comprehensive analyses of those in GCs may help elucidate the mechanism of carcinogenesis.

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Section: Epigenetic Aberrant In Gastric Cancermentioning

confidence: 99%

Section: Epigenetic Aberrant In Gastric Cancermentioning

confidence: 99%

Section: Genetic Aberrations In Gastric Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA Methylation and Genetic Aberrations in Gastric Cancer

et al. 2020

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“…Interaction of EBV episome and the host genome, in fact, could result in redistribution of histone marks. Using a panel of 14 GC cell lines, including three EBV positive, two immortalized gastric epithelial cell lines, and EBV-positive primary GC tissues, a recent chromosome conformation capture combined with high-throughput sequencing (Hi-C) study showed that the EBV genome, in particular the oriP region, preferentially associated with human chromosomes 2, 3, 4, 6, 7, and 13, and these EBV-interacting regions usually exhibited higher A-T content, reduced H3K9me3, as well as higher H3K27ac or H3K4me1 signals (106) (Figure 2). This study further showed that the domain and loop structure alterations by EBV infection could induce cancer-related gene expression including KLF5, TGFBR2, and MZT1 (106), suggesting the role of EBV in the regulation of gene expression through histone modification and chromatin conformation alteration.…”

Section: Redistribution Of Histone Marks and Interaction Of The Ebv Ementioning

confidence: 99%

The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies

Leong

Lung

2021

Front. Oncol.

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Epstein-Barr virus (EBV) infection is associated with a variety of malignancies including Burkitt’s lymphoma (BL), Hodgkin’s disease, T cell lymphoma, nasopharyngeal carcinoma (NPC), and ∼10% of cases of gastric cancer (EBVaGC). Disruption of epigenetic regulation in the expression of tumor suppressor genes or oncogenes has been considered as one of the important mechanisms for carcinogenesis. Global hypermethylation is a distinct feature in NPC and EBVaGC, whereas global reduction of H3K27me3 is more prevalent in EBVaGC and EBV-transformed lymphoblastoid cells. In BL, EBV may even usurp the host factors to epigenetically regulate its own viral gene expression to restrict latency and lytic switch, resulting in evasion of immunosurveillance. Furthermore, in BL and EBVaGC, the interaction between the EBV episome and the host genome is evident with respectively unique epigenetic features. While the interaction is associated with suppression of gene expression in BL, the corresponding activity in EBVaGC is linked to activation of gene expression. As EBV establishes a unique latency program in these cancer types, it is possible that EBV utilizes different latency proteins to hijack the epigenetic modulators in the host cells for pathogenesis. Since epigenetic regulation of gene expression is reversible, understanding the precise mechanisms about how EBV dysregulates the epigenetic mechanisms enables us to identify the potential targets for epigenetic therapies. This review summarizes the currently available epigenetic profiles of several well-studied EBV-associated cancers and the relevant distinct mechanisms leading to aberrant epigenetic signatures due to EBV.

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Association of tumors having Epstein–Barr virus in surrounding lymphocytes with poor prognosis

et al. 2022

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Infection with certain viruses is an important cause of cancer. The Pan‐Cancer Analysis of Whole Genomes (PCAWG) Consortium recently analyzed the whole‐genome sequencing (WGS) data from 2656 cases across 21 cancer types, and indicated that Epstein–Barr virus (EBV) is detected in many different cancer cases at a higher frequency than previously reported. However, whether EBV‐positive cancer cases detected by WGS‐based screening correspond to those detected by conventional histopathological techniques is still unclear. In this study, to elucidate the involvement of EBV in various cancers, we reanalyzed the WGS data of the PCAWG cohort combined with the analysis of clinical samples of gastric and pancreatic cancer in our cohort. Based on EBV copy number in each case, we classified tumors into three subgroups: EBV‐High, EBV‐Low, and EBV‐Negative. The EBV‐High subgroup was found to be EBV‐positive in the cancer cells themselves, whereas the EBV‐Low subgroup was EBV‐positive in the surrounding lymphocytes. Further, the EBV‐Low subgroup showed a significantly worse prognosis for both gastric cancer and across cancer types. In summary, we classified tumors based on EBV copy number and found a unique cancer subgroup, EBV‐positive in the surrounding lymphocytes, which was associated with a poor prognosis.

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Cross-species chromatin interactions drive transcriptional rewiring in Epstein–Barr virus–positive gastric adenocarcinoma

Cited by 79 publications

References 47 publications

DNA Methylation and Genetic Aberrations in Gastric Cancer

DNA Methylation and Genetic Aberrations in Gastric Cancer

The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies

Association of tumors having Epstein–Barr virus in surrounding lymphocytes with poor prognosis

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