Abstract 4246: Associations of Epstein-Barr virus (EBV)-positive gastric cancer with circulating mediators of inflammation and immune response
Authors: Camargo M. Constanza , Sivins Armands , Isajevs Sergejs , Rudzite Dace , Gulley Margaret , Offerhaus G. Johan , Leja Marcis , Rabkin Charles S. 
Published: July 2017

Epstein-Barr virus (EBV) positivity defines one of four major molecular types of gastric cancer in The Cancer Genome Atlas (TCGA). However, viral status is not routinely determined in clinical practice and tumor samples are not generally collected in epidemiologic research. Histologically, EBV-positive gastric cancer is characterized by prominent inflammatory infiltrate. In molecular analyses from TCGA, EBV-positive gastric cancer had significantly higher expression of several chemokines, chemokine receptors and programmed death-ligand 1 (PD-L1) as compared to other molecular types combined. We hypothesized that EBV tumor status may also be reflected in profiles of circulating chemokines and other markers of immune response. We have therefore evaluated pre-treatment EDTA plasma samples of gastric cancer patients from Latvia, including 28 with EBV-positive (as assessed by EBV RNA in situ hybridization) and 34 with EBV-negative tumors, frequency-matched by age, sex, anatomical subsite and Lauren histological type. We measured 92 markers using the Proseek Inflammation Panel I (Olink Proteomics, Uppsala, Sweden). We used logistic regression to model adjusted associations between tertiles of the markers and tumor EBV positivity. P&lt;0.05 was considered statistically significant. Nine markers had undetectable levels in all or almost all samples. Of 83 evaluable markers, 8 were significantly higher in patients with EBV-positive tumors vs. those with EBV-negative tumors, including Chemokine C-C motif ligand (CCL) 20 (odds ratio per tertile [OR]: 3.6; p-trend=0.001), Chemokine C-X-C motif ligand 19 (OR=3.6; p-trend=0.003), PD-L1 (OR=3.4; p-trend=0.004), interleukin (IL) 10 (OR=2.4; p-trend=0.019), CCL19 (OR=2.3; p-trend=0.019), CCL11 (OR=2.2; p-trend=0.026), IL-17A (OR=2.0; p-trend=0.038) and CCL8 (OR=1.9; p-trend=0.049). These eight markers were positively correlated with the 28 pair-wise Spearman correlations ranging from 0.14 - 0.71, of which 24 were statistically significant. A model combining the top three markers, CCL20, CXCL19 and PD-L1, discriminated tumor EBV status with an area under the receiver operating characteristics curve of 0.82. These data indicate that the local alterations of specific chemokines and PDL-1 characterizing EBV-positive gastric tumors are reflected in the systemic circulation. Profiling of these molecules may enable non-invasive diagnosis of EBV-positive gastric cancer and facilitate etiologic and translational studies in large-scale prospective cohorts that lack tumor specimens. Our findings provide additional support for evaluating PD-1 blockade and other immunomodulatory therapies for patients with EBV-positive gastric cancer.

Citation Format: M. Constanza Camargo, Armands Sivins, Sergejs Isajevs, Dace Rudzite, Margaret Gulley, G. Johan Offerhaus, Marcis Leja, Charles S. Rabkin. Associations of Epstein-Barr virus (EBV)-positive gastric cancer with circulating mediators of inflammation and immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4246. doi:10.1158/1538-7445.AM2017-4246