Gastric Adenocarcinomas Display Unique Human and Viral RNA Signatures Related to Epstein-Barr Virus Infection
Kimberly Woodward, Weihua Tang, Douglas R Morgan, Michael O Meyers, Ricardo L Dominguez, Pei-Fen Kuan, Hind Muallem, Margaret L Gulley. University of North Carolina, Chapel Hill, NC; Western Regional Hospital, Santa Rosa de Copan, Honduras
Background: Gastric carcinoma was diagnosed in an estimated 21,250 United States patients last year, with 10,340 attributable deaths. Disease pathogenesis is complex and likely represents the end point of interactions between environmental and host factors, including Epstein-Barr virus (EBV) and Helicobacter pylori infection, genetic susceptibility, and nitrate ingestion. Most patients present with advanced disease and then die of disease, indicating the need for earlier detection and better management strategies. RNA-based expression profiling shows promise for early detection, monitoring tumor burden, and predicting response to therapy.
Design: To promote assay development and validation, we used the Nanostring nCounter system to measure 96 RNAs, including non-coding and viral RNAs, in 116 paraffin-embedded gastric adenocarcinoma tissues that had been macrodissected to enrich for malignant cells.
Results: Expression patterns revealed four distinct molecular subtypes of gastric cancer. Molecular Group 4 (n=13) expressed both lytic and latent EBV genes and was downregulated for many factors previously reported to be gastric cancer-specific. Unlike EBV negative cancers, the EBV positive cancers lacked chromogranin A (CHGA) and they expressed CXCL1 and TRAF1, suggesting NFKB signaling downstream of viral LMP1. The majority of gastric cancers clustered into Molecular Group 1 (n=52) and overexpressed many genes previously reported to be associated with gastric carcinoma, including REG4 and CDH17, while Molecular Group 2 (n=24) lacked these two RNAs. Intermediate levels of lytic viral RNA were seen in groups 2 and 3 but these 2 groups differed from each other in levels of GPR183 (EBI2), an EBV-associated G-protein, and in the pro-apoptotic factor BCL2L11 (BIM). Given that the list of profiled genes was enriched for those that distinguish benign from malignant gastric tissue, it is not surprising that benign mucosa displayed an expression profile unlike that of the predominant group 1 cancers.
Conclusions: Overall, this study shows that molecular subtyping is feasible on paraffin-embedded biopsy or resection tissue and that gastric cancer is heterogeneous from a molecular standpoint. These findings may promote the development of screening tests for the major cancer subtypes and may help control cancer by tailoring therapy to the unique biochemical pathways that characterize a given patient's tumor.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 116, Monday Morning