Epigenetic alternate promoter utilization and association with PD-L1 expression in Epstein–Barr virus positive gastric cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15509-e15509
Author(s):  
Raghav Sundar ◽  
Aditi Qamra ◽  
Angie Lay Keng Tan ◽  
Shenli Zhang ◽  
Cedric Chuan Young Ng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Epstein Barr Virus ◽  
Checkpoint Inhibitors ◽  
Primary Resistance ◽  
Barr Virus ◽  
Alternate Promoter ◽  
Epstein Barr ◽  
Gastric Cancer Patients

e15509 Background: We recently elicited the role of epigenetic promoter alterations as a mechanism of immune-evasion and primary resistance to immune checkpoint inhibition in gastric cancer. High prevalence of epigenetic modifications are known to occur in Epstein-Barr virus associated gastric cancer (EBVaGC). EBVaGC has high response rates to anti-PD-1 immune checkpoint inhibitors and is associated with high levels of PD-L1 expression. However, not all EBVaGC express PD-L1 and mechanisms that mediate these phenomena are unknown. Methods: We performed NanoString profiling and PD-L1 immunohistochemistry (using Dako PD-L1 IHC 22C3) on tissue from gastric cancer patients undergoing primary tumor resections at Samsung Medical Centre, South Korea. NanoString panel was designed for 90 recurrent somatic alternate promoter-related genes, and immune-related genes including PD-L1. EBV status was determined using EBV-encoded RNA in situ hybridization and categorized as EBVaGC and EBV-negative. Samples in the top-quartile of alternate promoter utilization were classified as APhigh and the remaining APlow. Results: A total of 272 samples (EBVaGC n = 79; EBV-negative n = 193) were included in this study. EBVaGC had significantly higher PD-L1 expression (p < 0.001) compared to EBV-negative samples. APhigh group (n = 67) consisted of 61 EBV-negative and 6 EBVaGC samples. EBVaGC APhigh tumors had significantly lower PD-L1 transcript expression compared to EBVaGC APlow tumors (p = 0.011, Wilcoxon-rank sum). Similar correlation was also found with PD-L1 IHC combined positive score (CPS)(median CPS score 1 vs 8, p = 0.047). There was a trend towards poorer survival for EBVaGC APhigh tumors (vs EBVaGC APlow; HR 0.23, 95% CI: 0.046 – 1.23, p = 0.087). EBV-negative APhigh tumors also had lower PD-L1 expression (vs EBV-negative APlow; p = 0.046, Wilcoxon-rank sum). Conclusions: Increased utilization of epigenetic alternate promoter isoforms correlates with lower transcriptomic and protein expression of PD-L1 in EBVaGC. Here we describe a potential mechanism of immune-evasion to explain low immune-infiltration and PD-L1 expression that occurs in a group of EBVaGC that is traditionally considered highly immunogenic.

scholarly journals Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jieti Wang ◽  
Ruochen Li ◽  
Yifan Cao ◽  
Yun Gu ◽  
Hanji Fang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Epstein Barr Virus ◽  
Effector Memory ◽  
Feature Identification ◽  
Barr Virus ◽  
T Cell Infiltration ◽  
Epstein Barr ◽  
Gastric Cancer Patients

AbstractStudies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.

scholarly journals Efficacy of Immune Checkpoint Inhibitors in Metastatic Epstein-Barr Virus Associated Gastric Cancer (EBVaGC): A Case Series and Review of Literature

2021 ◽  
Author(s):  
Shimeng Liang ◽  
Weibing Leng ◽  
Dan Jiang ◽  
Ming Liu ◽  
Dan Cao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Immune Checkpoint Inhibitors ◽  
Epstein Barr Virus ◽  
Checkpoint Inhibitors ◽  
Case Series ◽  
Metastatic Gastric Cancer ◽  
Pooled Analysis ◽  
Barr Virus ◽  
Epstein Barr

Abstract Background Immunotherapy has revolutionized the treatment of malignant tumors. However, limited clinical data are available to report the efficacy of immune checkpoint inhibitors (ICIs) on Epstein-Barr virus-associated gastric carcinoma. Methods In this study, we report a case series of five patients with metastatic Epstein-Barr virus-associated gastric carcinoma who were treated with ICIs and to perform a pooled analysis of published cases to investigate the efficacy of ICIs in Epstein-Barr virus-associated gastric carcinoma patients. Results Between 2018 and 2020, five metastatic gastric cancer patients with EBV positivity who received PD-1 antibodies treatment were included in the analysis at the authors’ institution. Furthermore, we performed a pooled analysis of the contemporary literature. In our case series, two patients experienced partial response (PR); one patient achieved complete response (CR), whereas two patients had progression disease (PD), resulting an ORR of 60%. In the pooled analysis of all 36 patients, ORR was 48.6% (17/35). For the first line and later lines, it was 75% (3/4) and 45.2% (14/31) respectively. The ORR was 46.7% (14/30) for ICIs monotherapy and improved to 60% (3/5) by combination with chemotherapy. Conclusions These results demonstrated that an EBV-positive status was a reliable biomarker for immunotherapy in metastatic gastric cancer, especially for monotherapy. Immunotherapy combined with chemotherapy may be a better strategy, warranting further large-scale clinical trials for validation.

scholarly journals Comprehensive Multi-Omics Analysis Reveals Aberrant Metabolism of Epstein–Barr-Virus-Associated Gastric Carcinoma

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1220 ◽  
Author(s):  
Yoon ◽  
Kim ◽  
Long ◽  
Min ◽  
Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Carcinoma ◽  
Epstein Barr Virus ◽  
Tissue Samples ◽  
Barr Virus ◽  
Advanced Gastric Carcinoma ◽  
Metabolic Genes ◽  
Epithelial Cell Lines ◽  
Epstein Barr ◽  
Gastric Cancer Patients

The metabolic landscape of Epstein–Barr-virus-associated gastric cancer (EBVaGC) remains to be elucidated. In this study, we used transcriptomics, metabolomics, and lipidomics to comprehensively investigate aberrant metabolism in EBVaGC. Specifically, we conducted gene expression analyses using microarray-based data from gastric adenocarcinoma epithelial cell lines and tissue samples from patients with clinically advanced gastric carcinoma. We also conducted complementary metabolomics and lipidomics using various mass spectrometry platforms. We found a significant downregulation of genes related to metabolic pathways, especially the metabolism of amino acids, lipids, and carbohydrates. The effect of dysregulated metabolic genes was confirmed in a survival analysis of 3951 gastric cancer patients. We found 57 upregulated metabolites and 31 metabolites that were downregulated in EBVaGC compared with EBV-negative gastric cancer. Sixty-nine lipids, mainly ether-linked phospholipids and triacylglycerols, were downregulated, whereas 45 lipids, mainly phospholipids, were upregulated. In total, 15 metabolisms related to polar metabolites and 15 lipid-associated pathways were involved in alteration of metabolites by EBV in gastric cancer. In this work, we have described the metabolic landscape of EBVaGC at the multi-omics level. These findings could help elucidate the mechanism of EBVaGC oncogenesis.

scholarly journals Acute cerebellar ataxia due to Epstein-Barr virus under administration of an immune checkpoint inhibitor

2019 ◽  
Vol 12 (12) ◽  
pp. e231520 ◽  
Author(s):  
Hirotaka Saikawa ◽  
Hiromi Nagashima ◽  
Tetsuya Maeda ◽  
Makoto Maemondo
Keyword(s):  
Adverse Events ◽  
Cerebellar Ataxia ◽  
Immune Checkpoint ◽  
Epstein Barr Virus ◽  
Checkpoint Inhibitors ◽  
Pulse Therapy ◽  
Steroid Pulse ◽  
Barr Virus ◽  
Acute Cerebellar Ataxia ◽  
Epstein Barr

A 71-year-old male patient with adenocarcinoma of the lung and contralateral lung metastasis under administration of pembrolizumab had symptoms of cerebellar ataxia. We suspected that the symptoms were immune-related adverse events (irAE), but the patient was subsequently diagnosed as cerebellitis due to Epstein-Barr virus (EBV) infection. After steroid pulse therapy, the symptoms of cerebellar ataxia improved immediately. Immune checkpoint inhibitors (ICI) can induce neurological adverse events and cause acute cerebellar ataxia. Initially, irAEs were suspected in this case. His clinical data suggested that reactivation of the virus had occurred because the ICI affected his immune system. This is the first report of a case of acute cerebellar ataxia due to EBV under administration of an ICI.

scholarly journals Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications

ESMO Open ◽  
2019 ◽  
Vol 4 (3) ◽  
pp. e000470 ◽  
Author(s):  
Carolina Martinez-Ciarpaglini ◽  
Tania Fleitas-Kanonnikoff ◽  
Valentina Gambardella ◽  
Marta Llorca ◽  
Cristina Mongort ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Immune Checkpoint ◽  
Epstein Barr Virus ◽  
In Situ Hybridisation ◽  
Immune Checkpoint Blockade ◽  
Diffuse Type ◽  
Barr Virus ◽  
Epstein Barr ◽  
Mmr Proteins

BackgroundThe molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors.Material and methodsWe collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation.ResultsForty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable tumour-specific survival (TSS) in stages I–III (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04).ConclusionsThe MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.

scholarly journals PD-L1 Expression Associated with Epstein—Barr Virus Status and Patients’ Survival in a Large Cohort of Gastric Cancer Patients in Northern Brazil

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3107
Author(s):  
Caroline de Fátima Aquino Moreira-Nunes ◽  
Cláudia Nazaré de Souza Almeida Titan Martins ◽  
Danielle Feio ◽  
Isamu Komatsu Lima ◽  
Leticia Martins Lamarão ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Survival Data ◽  
Epstein Barr Virus ◽  
Gastric Neoplasms ◽  
Probability Of Survival ◽  
Barr Virus ◽  
Kaplan Meier ◽  
Epstein Barr ◽  
Gastric Cancer Patients

Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that consists of tumors infected with the Epstein–Barr virus (EBV) and is characterized mainly by the overexpression of programmed cell death protein-ligand-1 (PD-L1). In the present study, we present histopathological and survival data of a thousand GC patients, associated with EBV status and PD-L1 expression. Of the thousand tumors analyzed, 190 were EBV-positive and the vast majority (86.8%) had a high relative expression of mRNA and PD-L1 protein (p < 0.0001) in relation to non-neoplastic control. On the other hand, in EBV-negative samples, the majority had a low PD-L1 expression of RNA and protein (p < 0.0001). In the Kaplan–Meier analysis, the probability of survival and increased overall survival of EBV-positive GC patients was impacted by the PD-L1 overexpression (p < 0.0001 and p = 0.004, respectively). However, the PD-L1 low expression was correlated with low overall survival in those patients. Patients with GC positive for EBV, presenting PD-L1 overexpression can benefit from immunotherapy treatments and performing the quantification of PD-L1 in gastric neoplasms should be adopted as routine.

scholarly journals Association between Epstein-Barr Virus Infection and Gastric Cancer: A Systematic Review and Meta-analysis

2020 ◽  
Author(s):  
Ahmad Tavakoli ◽  
Seyed Hamidreza Monavari ◽  
Farid Solaymani Mohammadi ◽  
Seyed Jalal Kiani ◽  
Saber Armat ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Epstein Barr Virus ◽  
The Body ◽  
Matched Pairs ◽  
Barr Virus ◽  
Ebv Infection ◽  
Analytic Review ◽  
Epstein Barr ◽  
Gastric Cancer Patients

Abstract Background: Numerous studies conducted over the past 30 years have pointed to the presence of Epstein–Barr virus (EBV) in gastric cancer samples. This study was aimed to provide a meta-analytic review of the prevalence of EBV in gastric cancer patients, and to clarify the relationship between EBV infection and gastric cancer. Methods: A literature search was performed electronically using online databases for English language publications until July 1, 2019. The pooled EBV prevalence and 95% confidence intervals (CIs) were estimated using a random effects model. To determine the association between EBV and gastric cancer, pooled odds ratio (OR) and its 95% CI were computed for case-control studies with matched pairs design. Results: The pooled prevalence of EBV in 20411 gastric cancer patients was 8.78% (95% CI: 7.75-9.93%; I 2 =83.0%). The proportion of EBV-associated gastric cancer among male cases was significantly higher than among female cases (10.85%, vs 5.72%) ( P <0.01). EBV was more prevalent in the cardia (12.47%) and in the body (11.68%) compared to the antrum (6.29%) ( P <0.01). There were 20 studies with matched pairs design, including tumor and tumor-adjacent normal tissue pairs from 4116 gastric cancer patients. The pooled OR between EBV infection and gastric cancer risk was 18.56 (95% CI: 15.68–21.97; I 2 = 55.4%). Conclusion: EBV infection is associated with more than 18 times increase risk of gastric cancer. Although the prevalence of EBV was higher in male patients than in female patients with gastric cancer, women are more likely than men to develop EBV-associated gastric cancer.

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