Julie L. Ryan, Ph.D.

Dissertation research performed under the direction of Margaret L. Gulley

ABSTRACT
    Gastric cancer is the fourth most common type of cancer and the second leading cause of cancer death worldwide. Patients often present with advanced and incurable disease. Even with resection and/or chemotherapy, high rates of recurrence result in poor overall survival. Clearly better management options are needed. One promising avenue is to take advantage of the presence of Epstein-Barr virus (EBV) as a tumor marker and a target for therapy. EBV is present in the malignant cells of about 10% of gastric adenocarcinomas, but how the virus might cause or promote cancer progression remains unknown. Additionally, whether EBV infects benign gastric epithelium or lesions that predispose to cancer, such as gastritis, is ambiguous. Furthermore, it is unclear whether EBV is being missed in some gastric lesions due to insensitive test methods or partial EBV genome loss or rearrangement. The long-term goal of this research project was to better characterize the presence of EBV in lesional tissue and to understand the mechanisms by which the virus might contribute to carcinogenesis. Quantitative real-time PCR assays targeting disparate parts of the EBV genome ( BamH1W, EBNA1, LMP1, LMP2, BZLF1, EBER1 ) and a rearranged partial EBV genome ( WZhet ), as well as traditional EBER in situ hybridization, and immunohistochemistry (targeting BZLF1, BMRF1, LMP1, LMP2A) were used to detect and localize EBV infection in gastric adenocarcinomas (from geographic regions of low and high incidence), and several types of inflammatory gastric lesions. The hypothesis was that EBV is more pertinent in these lesions than previously recognized, and that it influences key cellular growth regulatory pathways that are involved in gastric carcinogenesis. To identify these pathways, in vitro mRNA expression differences in EBV-positive and EBV-negative gastric cancers were examined using low-density cDNA microarrays and semi-quantitative reverse transcription PCR. EBV-specific alterations in gene expression suggest that the virus influences critical cell growth regulatory pathways. The results of this study expand our understanding of gastric cancer etiology, and the results could be used as a foundation for further research aimed at improving diagnosis and treatment of gastric cancer.