Association of single nucleotide polymorphism rs2065955 of the filaggrin gene with susceptibility to Epstein-Barr virus-associated gastric carcinoma and EBV-negative gastric carcinoma.
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ABSTRACT:
SUBMITTER: Kuang X
PROVIDER: S-EPMC8193425 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAround 10% of gastric carcinomas (GC) contain Epstein-Barr virus (EBV) DNA. We characterized the GC-specific antibody response to this common infection, which may provide a noninvasive method to detect EBV-positive GC and elucidate its contribution to carcinogenesis.MethodsPlasma samples from EBV-positive (n = 28) and EBV-negative (n = 34) Latvian GC patients were immune-profiled against 85 EBV proteins on a multi-microbial Nucleic Acid Programmable Protein Array (EBV-NAPPA). Antibody responses were normalized for each sample as ratios to the median signal intensity (MNI) across all antigens, with seropositivity defined as MNI ≥ 2. Antibodies with ≥ 20% sensitivity at 95% specificity for tumor EBV status were verified by enzyme-linked immunosorbent assay (ELISA) and validated in independent samples from Korea and Poland (n = 24 EBV-positive, n = 65 EBV-negative).ResultsForty anti-EBV IgG and eight IgA antibodies were detected by EBV-NAPPA in ≥ 10% of EBV-positive or EBV-negative GC patients, of which nine IgG antibodies were discriminative for tumor EBV status. Eight of these nine were verified and seven were validated by ELISA: anti-LF2 (odds ratio = 110.0), anti-BORF2 (54.2), anti-BALF2 (44.1), anti-BaRF1 (26.7), anti-BXLF1 (12.8), anti-BRLF1 (8.3), and anti-BLLF3 (5.4). The top three had areas under receiver operating characteristics curves of 0.81-0.85 for distinguishing tumor EBV status.ConclusionsThe EBV-associated GC-specific humoral response was exclusively directed against lytic cycle immediate-early and early antigens, unlike other EBV-associated malignancies such as nasopharyngeal carcinoma and lymphoma where humoral response is primarily directed against late lytic antigens. Specific anti-EBV antibodies could have utility for clinical diagnosis, epidemiologic studies, and immune-based precision treatment of EBV-positive GC.
| S-EPMC8206016 | biostudies-literature
Project description:BackgroundEpstein-Barr virus (EBV)-positive gastric cancers have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serologic profiles may inform viral contribution to carcinogenesis.MethodsWe compared humoral responses of EBV-positive (n = 67) and EBV-negative (n = 137) patients with gastric cancer from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D), and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. OR of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in gastric cancer.ResultsConsistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and EBV-negative tumors for anti-EA-D (97% vs. 67%, respectively, P < 0.001) and anti-ZEBRA (97% vs. 85%, respectively, P = 0.009). Adjusted ORs (vs. T1) for patients with EBV-positive versus EBV-negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR = 0.16, P = 0.021). Anti-p53 prevalence from the literature was 15%.ConclusionsThese serologic patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype.ImpactAnti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive gastric cancer for targeted therapies.
| S-EPMC8272980 | biostudies-literature
Project description:Epstein-Barr virus (EBV) is linked to the development of a variety of malignancies, including EBV-associated gastric carcinoma (EBVaGC). In this study, EBVaGC was detected in 15 (7.3%) of 206 GC cases. To identify the EBV genomic variation, EBV genomic sequences isolated from 9 EBVaGC biopsy specimens were successfully retrieved, designated EBVaGC1 to EBVaGC9. By comparative analysis of these strains with another 6 completely sequenced EBV strains, EBV-wild type, B95-8, AG876, GD1, GD2, and HKNPC1, it was demonstrated that EBVaGC1 to 9 were most closely related to the GD1 strain. Phylogenetic analysis of the GC biopsy specimen-derived EBV (GC-EBV) genomes was subsequently performed to assess their genomic diversity and it exhibited the greatest divergence from the type 2 strain, AG876. Compared with the reference EBV strain GD1, they harbored 961 variations in total, including 919 substitutions, 23 insertions, and 19 deletions. Single nucleotide polymorphism (SNP) density varied substantially across all known open reading frames and was highest in latency-associated genes. Moreover, we identified 2 interstrain recombinants at the EBNA1 locus, which provided a further mechanism for the generation of diversity. Some T-cell epitope sequences in EBNA1 and LMP2A genes showed extensive variation across strains, which implied their importance in the development of vaccines and T-cell therapy. In conclusion, we reported the first genome-wide view of sequence variation of EBV isolated from primary EBVaGC biopsy specimens, which might serve as an effective method for further understanding the genomic variations contribute to EBVaGC carcinogenesis and treatment.
| S-EPMC4826252 | biostudies-literature
Project description:The Epstein-Barr virus (EBV) SM protein is essential for lytic EBV DNA replication and virion production. When EBV replication is induced in cells infected with an SM-deleted recombinant EBV, approximately 50% of EBV genes are expressed inefficiently. When EBV replication is rescued by transfection of SM, SM enhances expression of these genes by direct and indirect mechanisms. While expression of most EBV genes is either unaffected or enhanced by SM, expression of several genes is decreased in the presence of SM. Expression of BHRF1, a homolog of cellular bcl-2, is particularly decreased in the presence of SM. Investigation of the mechanism of BHRF1 downregulation revealed that SM downregulates expression of the immediate-early EBV transactivator R. In EBV-infected cells, R-responsive promoters, including the BHRF1 and SM promoters, were less active in the presence of SM, consistent with SM inhibition of R expression. SM decreased spliced R mRNA levels, supporting a posttranscriptional mechanism of R inhibition. R and BHRF1 expression were also found to decrease during later stages of EBV lytic replication in EBV-infected lymphoma cells. These data indicate that feedback regulation of immediate-early and early genes occurs during the lytic cycle of EBV regulation.
| S-EPMC2715772 | biostudies-literature
Project description:Various polymorphisms in toll-like receptor (TLR) genes have been identified and associated with susceptibility to various malignancies, such as gastric carcinoma (GC), breast cancer, and prostate cancer. However, little is known about the polymorphisms of TLR genes and the susceptibility to GC in Northern China, especially to Epstein-Barr virus-associated GC (EBVaGC). We focused on the association with susceptibility to GC, especially to EBVaGC.Polymorphisms of the TLR2, 3, 4, and 9 genes were measured in 52 cases of EBVaGC and 157 cases of EBV-negative GC (EBVnGC). Ninety-four peripheral blood samples from healthy individuals were also examined.For the TLR2 gene (196 to 174 del), there was no significant difference between the GC group and control group in genotype, but there was a significant difference in the del allele. As for the TLR3 gene (c. 1377C/T), there were significant differences between the GC group and the control group in both genotype and allelic frequency. No SNPs single nucleotide polymorphisms (SNPs) were found in the TLR4 gene at the sites Asp299Gly and Thr399Ile. As for TLR9 1486T/C (rs187084) and C2848T (rs352140), there was also no association between the GC group and control. In all of the indicators, there were no significant differences between EBVaGCs and EBVnGCs.The TLR3 gene (c. 1377C/T) polymorphisms and the del allele of the TLR2 gene ( 196 to 174) were both associated with susceptibility to GC in Shangdong Province of Northern China. There was no interaction between EBV and TLR gene polymorphisms in EBVaGC.
| S-EPMC4392582 | biostudies-literature
Project description:Cancer stem cells (CSCs) are cancer-initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5-fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU-4th, which displays properties of CSCs and mainly consists of CD44+ CD24- cells. In SNU-4th cells, an EBV-encoded circRNA, ebv-circLMP2A, expression increased and plays crucial roles in inducing and maintaining stemness phenotypes through targeting miR-3908/TRIM59/p53 axis. Additionally, high expression of ebv-circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv-circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.
| S-EPMC7534631 | biostudies-literature
Project description:Cancer stem cells (CSCs) are cancer initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5-fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU-4th, which displays properties of CSCs and mainly consists of CD44+CD24- cells. In SNU-4th cells, the expression of an EBV-encoded circRNA, ebv-circLMP2A, is strongly increases, which plays crucial roles in inducing and maintaining stemness phenotypes by targeting the miR-3908/TRIM59/p53 axis. Additionally, high expression of ebv-circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv-circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.
| S-SCDT-EMBOR-2019-49689V1 | biostudies-other
Project description:OBJECTIVE:Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (?45?years) compared with an average-onset cohort (?55?years) and characterize the clinicopathologic pattern of young-onset GC. METHODS:Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records. RESULTS:Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p?=?0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p?=?0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68?years). MSI-H was found only in the average-onset cohort [0% vs 27%, p?=?0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p?=?0.002). CONCLUSION:Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.
| S-EPMC6961297 | biostudies-literature
Project description:BackgroundEpstein-Barr virus (EBV) has a biphasic infection cycle consisting of a latent and a lytic replicative phase. The product of immediate-early gene BRLF1, Rta, is able to disrupt the latency phase in epithelial cells and certain B-cell lines. The protein Rta is a frequent target of the EBV-induced cytotoxic T cell response. In spite of our good understanding of this protein, little is known for the gene polymorphism of BRLF1.ResultsBRLF1 gene was successfully amplified in 34 EBV-associated gastric carcinomas (EBVaGCs), 57 nasopharyngeal carcinomas (NPCs) and 28 throat washings (TWs) samples from healthy donors followed by PCR-direct sequencing. Fourteen loci were found to be affected by amino acid changes, 17 loci by silent nucleotide changes. According to the phylogenetic tree, 5 distinct subtypes of BRLF1 were identified, and 2 subtypes BR1-A and BR1-C were detected in 42.9% (51/119), 42.0% (50/119) of samples, respectively. The distribution of these 2 subtypes among 3 types of specimens was significantly different. The subtype BR1-A preferentially existed in healthy donors, while BR1-C was seen more in biopsies of NPC. A silent mutation A/G was detected in all the isolates. Among 3 functional domains, the dimerization domain of Rta showed a stably conserved sequence, while DNA binding and transactivation domains were detected to have multiple mutations. Three of 16 CTL epitopes, NAA, QKE and ERP, were affected by amino acid changes. Epitope ERP was relatively conserved; epitopes NAA and QKE harbored more mutations.ConclusionsThis first detailed investigation of sequence variations in BRLF1 gene has identified 5 distinct subtypes. Two subtypes BR1-A and BR1-C are the dominant genotypes of BRLF1. The subtype BR1-C is more frequent in NPCs, while BR1-A preferentially presents in healthy donors. BR1-C may be associated with the tumorigenesis of NPC.
| S-EPMC3002924 | biostudies-literature
Project description:Gastric carcinoma (GC) is a leading cause of mortality. 10% of GC cases are related with EBV (Epstein-Barr virus) infection. The detailed mechanistic roles EBV genes play and especially the interaction between the viral genes and human genes in GC remain unclear. In this study, raw fastq data from 285 GC samples were downloaded from TCGA (The Cancer Genome Atlas), including 25 EBV positive (EBV+) GC samples and 260 EBV negative (EBV-) GC samples. RNA-seq based expression data were generated for both human genes (among all the samples) and for the EBV genes (among the 25 EBV+ samples). Bioinformatics analyses were performed to identify differentially expressed (DEx) human genes and DEx KEGG pathways in EBV+ vs. EBV- samples and co-expressed human gene modules and hub genes among the DEx genes. Within the EBV+ samples, analyses were conducted to find correlation between EBV gene expression and the human gene expression modules, between EBV gene expression and the human hub genes, and between EBV gene expression and the DEx human pathways. EBV genes LMP-1, BALF1 and BALF2 were found to have significant correlation with human hub genes, CNTD2 and VANGL2. EBV genes BALF4 and BALF5 were found to correlate with human pathways, including Jak-STAT signaling and Phosphatidylinositol Signaling System. Our study has revealed the coordinated expression patterns between EBV and human GC transcriptome and identified several key EBV genes that may play an important role in EBV+ GC pathogenesis through their interactions with human genes and pathways.
| S-EPMC5503541 | biostudies-literature