Genomic assays for Epstein–Barr virus-positive gastric adenocarcinoma

Gulley, Margaret L.

doi:10.1038/emm.2014.93

Cited by 61 publications

(55 citation statements)

References 118 publications

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“…EBV gastric cancers having a more extensive pattern of methylation of promoter and non-promoter CpG islands. 22 In fact, EBV gastric cancers are almost exclusive of the microsatellite-instable phenotype. 6,[23][24][25] A series of characteristics are important to underscore; EBV gastric cancers lack RHOA mutations; 6,23,24 however, a decreased expression of RHOA (and CDH1) may be seen secondary to hypermethylation of the gene or its promoter.…”

Section: Discussionmentioning

confidence: 99%

A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. Gastric carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Despite better control over known risk factors and development of new chemotherapeutic and targeted agents, in the United States, the 5-year overall survival for gastric cancer patients is only 29%. 1 With regard to patient stratification, although several morphologic classifications have been developed, one broadly used system is the Lauren classification, which divides gastric adenocarcinoma into intestinal and diffuse types. 2 The simple two-tiered classification gives a general understanding of the histogenesis and biology of gastric cancer, and has been particularly helpful in evaluating the epidemiologic data. Another widely used system is the WHO classification, which is based on more precise histologic patterns. It is an all-inclusive system, which recognizes all the rare subtypes that were not identified in the Lauren classification. 3 Nevertheless, its clinical utility is doubtful as there is little difference in outcomes between the distinct histological subgroups.Following the successful Trastuzumab for Gastric Cancer (ToGA) trial, the only validated predictive biomarker for personalized therapy of gastric cancer is limited to human epidermal growth factor receptor (Her2) protein expression. 4 Recently, anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody (ramucirumab) has been FDA approved, and anti-epidermal growth factor receptor (EGFR) an...

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Section: Discussionmentioning

confidence: 99%

A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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“…Genomic tests such as the GastroGenus Gastric Cancer Classifier analyse formalin-fixed cancer tissue and may be more clinically relevant [23]. Next generation sequencing can identify EBV-positive gastric tumours by quantifying viral sequences in genomic data [24].…”

Section: Gastro-oesophageal Cancermentioning

confidence: 99%

PD-1 and PD-L1 blockade in gastrointestinal malignancies

Lote

Cafferkey

Chau

2015

Cancer Treatment Reviews

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“…14 Prior studies of lymphoma malignancies suggested EBV-associated upregulation of PD-L1 on the cell surface, which is IFNg-mediated, and thus inhibits killing of infected cells by cytotoxic T cells expressing PD-1. 15 Therefore, we hypothesis that the function of EBV-specific CTLs may be affected by the acquired immune resistance indicated by the upregulation of PD-1 on CTLs and we assumed that blocking the interaction between PD-1 and PD-L1/L2 could augment the antitumor immune responses in EBVaGC.…”

Section: Introductionmentioning

confidence: 99%

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

Zou

Chen

et al. 2016

OncoImmunology

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The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1 pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC. These studies reveal possibility of generating PD-1-disrupted CTL by CRISPR-Cas9 system and demonstrate enhanced immune response of these PD-1-disrupted CTLs to the EBV-LMP2A antigen and superior cytotoxicity to the EBV-positive gastric cancer cell. In addition, when combined with low-dose radiotherapy, these PD-1-disrupted CTLs mediated an impressive antitumor effect in a xenograft mouse model of EBVaGC. Taken together, these studies illustrate PD-1/PD-L1-mediated immune tolerance of EBVaGC and provide a new strategy for targeting immune checkpoints to break the tolerance for the T cell-based adoptive therapy.

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Genomic assays for Epstein–Barr virus-positive gastric adenocarcinoma

Cited by 61 publications

References 118 publications

A protein and mRNA expression-based classification of gastric cancer

A protein and mRNA expression-based classification of gastric cancer

PD-1 and PD-L1 blockade in gastrointestinal malignancies

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

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