Clinical utility of circulating cell-free Epstein-Barr virus DNA in patients with gastric cancer.

Katsutoshi Shoda,Hidekazu Hiramoto,Toshiyuki Kosuga,Hirotaka Konishi,Tomohiro Arita,Shuhei Komatsu,Yuji Fujita,Kiyoshi Masuda,Atsushi Shiozaki,Eigo Otsuji,Kazuma Okamoto,Issei Imoto,Junichi Hamada,Daisuke Ichikawa

doi:10.18632/oncotarget.15675

Katsutoshi Shoda, Hidekazu Hiramoto + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.15675

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Abstract

Recent comprehensive molecular subtyping of gastric cancer (GC) identified Epstein–Barr virus (EBV)-positive tumors as a subtype with distinct salient molecular and clinical features. In this study, we aimed to determine the potential utility of circulating cell-free EBV DNA as a biomarker for the detection and/or monitoring of therapeutic response in patients with EBV-associated gastric carcinoma (EBVaGC). The EBV genes-to-ribonuclease P RNA component H1 ratios (EBV ratios) in the GC tumors and plasma samples were determined by quantitative real-time polymerase chain reaction in 153 patients with GC, including 14 patients with EBVaGC diagnosed by the conventional method. Circulating cell-free EBV DNA was detected in 14 patients with GC: the sensitivity and specificity of detection were 71.4% (10/14) and 97.1% (135/139), respectively. Plasma EBV ratios were significantly correlated with the size of EBVaGC tumors, and the plasma EBV DNA detected before surgery in EBVaGC cases disappeared after surgery. Patients with EBVaGC may have a better prognosis, but circulating cell-free EBV DNA had no or little impact on prognosis. In addition, repeated assessment of the plasma EBV ratio in EBVaGC showed a decrease and increase in plasma EBV DNA after treatment and during tumor progression/recurrence, respectively. These results suggest the potential utility of circulating cell-free DNA to reveal EBV DNA for the identification of the EBVaGC subtype and/or for real-time monitoring of tumor progression as well as treatment response in patients with EBVaGC.

Highlights

Gastric cancer (GC) is the fifth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide [1]
A previous study showed that Epstein–Barr virus (EBV) DNA levels generally reflect the EBV-encoded small RNAs (EBER) status, and a panel of at least two real-time quantitative polymerase chain reaction (rqPCR) assays is recommended for the sensitive identification of the infected cancers [14]
Latent membrane protein 1 (LMP1) and Epstein–Barr nuclear antigen 1 (EBNA1) levels were assessed to detect the presence of EBV DNA, and EBV DNA positivity was defined as a positive result in both the rqPCR assays

Summary

Introduction

Gastric cancer (GC) is the fifth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide [1]. It has been shown that “liquid biopsy” using circulating cell-free DNA (cfDNA) could constitute a new paradigm for the study of clonal evolution in human cancers [5]. Monitoring circulating cell-free EBV DNA can be an effective method for distinguishing diseaseassociated EBV reactivation from incidental presence of EBV in benign B lymphocytes as well as for diagnostic screening and monitoring of EBV-associated diseases such as Hodgkin's lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma [8,9,10], little has been done to evaluate the role of EBV testing in the diagnosis and monitoring of GC [11].

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