EBV as a potential risk factor for hepatobiliary system cancer: A meta-analysis with 918 cases

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Abstract

Objectives

Hepatobiliary system cancer, which includes hepatocellular carcinoma (HCC), cholangiocarcinoma, and gallbladder carcinoma, has an increase of incidence and mortality due to various risk factors. Epstein-Barr virus (EBV) is associated with various types of lymphomas and carcinomas, which is also acknowledged as the first-discovered human tumor virus. Despite this, there is no systematic analysis about the relationship between the infection of EBV and hepatobiliary system cancer. The aim of this meta-analysis is to explore the significance of EBV infection in the development of hepatobiliary system cancer by evaluating the EBV infection ratio.

Methods

A systematic search of PubMed, Embase, Cochrane Library, as well as China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wan Fang, and China Biology Medicine databases was conducted. The EBV infection ratio and 95% confidence intervals (CIs) in hepatobiliary system cancer was evaluated. The I2 statistic was used to represent heterogeneity. Through meta-regression, stratified analyses were applied to find out heterogeneity’s sources. Odds ratios (ORs), 95% CIs of EBV infection in case-control studies were calculated.

Results

Altogether, 15 studies were included containing a total of 918 cases and 157 controls. The whole infection ratio of EBV was 23% (95% CI: 13%, 33%, I2 = 95.7%, P < 0.001) among all the patients. Comparable EVB infection ratios were observed in hepatobiliary system cancer as divided into different subtypes. The five case-control studies were epitomized to a pooled OR of 9.35 (95%CI: 2.95, 29.61, I2 = 20.1%, P < 0.286).

Conclusion

EBV may be a potentially risk factor in the process of hepatobiliary system cancer. The prospective molecular mechanism remains to be explored.

Introduction

Hepatobiliary system cancer, which includes hepatocellular carcinoma (HCC), cholangiocarcinoma, and gallbladder carcinoma, has an increase of incidence and mortality due to various risk factors. Liver cancer, including HCC and cholangiocarcinoma, is one of the most common malignancies worldwide, which occurs more often in male than female, and more frequent in developing countries than developed ones. Areas in the East and Southeast have the highest rates of liver cancer, with more than half of the cases and deaths occurring in China. In the United States, estimated deaths of liver cancer in men and women are 19610 and 9310 in 2017, respectively. [[2], [3], [4]] Separately speaking, HCC in liver cancer is the most common class of liver malignancies, accounting for 85–90% of cases, with a high morbidity and mortality [[5], [6], [7], [8], [9], [10], [11]].Cholangiocarcinoma is another type of liver cancer which arises from the epithelium of the bile duct and accounts for 5–10% of liver cancer cases [[12], [13], [14]].Besides the above two subtypes of cancer, gallbladder carcinomas is also a subtype in the hepatobiliary system cancer, which has a capacity of high invasiveness, moreover, owning to late diagnosis and early metastasis, gallbladder carcinoma becomes an aporia in clinical work [[15], [16], [17], [18]].All of these three types of carcinomas can be categorized under hepatobiliary system cancer, whose incidence and mortality continue to rise because of various risk factors, including some virus.

Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is a family member of the gamma-herpes virus family, which infects more than 90% of the human population. EBV is closely associated with lymphoid and epithelial malignancies and causes 1.8% of all cancer-associated deaths in the world. [19,20]. Lymphoid malignancies including Burkitt’s lymphoma and Hodgkin’s lymphoma are well-known to be relevant to EBV infection, as well as some other carcinomas, including nasopharyngeal and gastric carcinomas [[21], [22], [23], [24]].

To date, several meta-analyses have been performed to confirm the relationship between EBV infection and carcinogenesis or prognosis of patients, including cancers of stomach, nasopharyngeal and breast, as well as Hodgkin’s and non-Hodgkin’s lymphomas. [[25], [26], [27], [28], [29], [30], [31], [32]] Previously, only single studies were performed to explore the relationship between EBV and HCC or cholangiocarcinoma with small sample sizes, which could not reach convincing conclusions. Furthermore, there is no meta-analysis focusing on the role of EBV infection in hepatobiliary system cancer.

Hence, we performed this meta-analysis to summarize the correlation with EBV infection and hepatobiliary system cancer and, thereby, shed more light on carcinogenicity of EBV in these diseases. We hope that this study will lead us in a direction to facilitate the research of EBV-associated hepatobiliary system malignancies, which can improve the diagnosis and therapies used for hepatobiliary system cancer.

Section snippets

Search strategy

A systematic literature search was conducted to screen all the applicable studies published before October 20, 2018 and the databases included PubMed, Embase, Cochrane Library, as well as China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wan Fang, and China Biology Medicine databases. The following searching strategy was used: “Burkitt lymphoma virus” or “E-B virus” or “infectious mononucleosis virus” or “Epstein-Barr virus” or “human herpes virus 4″ or “HHV-4″ or “Burkitt herpes

Eligible studies

The procedure of the meta-analysis was depicted in Fig. 1. A total of 1655 related publications were identified based on the primary search strategy. With the titles and abstracts being glanced over, 188 references were regarded as eligible in accordance with the above criteria. By reviewing the full text rigorously, 173 papers were eliminated, which included 62 studies with deficient information, 12 studies being conducted in non-human tissues, 29 reduplicated studies, 30 studies detecting EBV

Discussion

Among the hepatobiliary system cancers, liver cancer is the second leading cause of malignancy-related death worldwide [[33] [34],]. China has a high incidence of liver cancer that accounts for over 55% of the cases all over the whole world. [35] The occurrence and development is caused by multiple factors and multiple gene regulation process in liver cancers [36]. According to the originating sources, liver cancer can grow from hepatic or epithelial cells of the biliary tract. As the biliary

Acknowledgement

The study was supported by the Fund of Youth Science Foundation of Guangxi Medical University, China (GXMUYSF201507).

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