Molecular Subclasses of Non-keratinizing Nasopharyngeal Carcinoma Delineate a Pattern of Disease Progression, and Associate with Epstein - Barr Virus Load

Background Nasopharyngeal carcinoma, common in Southeast Asia, is mainly a non-keratinizing, squamous cell carcinoma (NK-NPC) and clinically heterogeneous. Methods Herein, we analyzed three human gene expression microarray datasets characterizing 81 NK-NPC tumors and 21 normal nasopharyngeal (NP) tissues to identify molecular subtypes of NK-NPC. In one of the datasets, QRT-PCR measurement of expression of 10 Epstein-Barr virus (EBV) latent genes in the same cohort (including 31 NK-NPC tumors and 10 NP tissues) was also available. Results NK-NPC tumors were clearly grouped into two classes, in which one class of tumor was grouped together with NP tissues. NK-NPC subclasses were independent from TNM stages. Type I NK-NPC (NK-NPC_I) had a low EBV load, while Type II NK-NPC (NK-NPC_II) had a high EBV load. Gene Set Enrichment Analysis (GSEA) showed that NK-NPC_I may be associated with normal epithelium-like, enhanced immune response, and good survival; while NK-NPC_II was associated with escape of immunosurveillance, cell proliferation, cancer stem cell (CSCs) enrichment, high metastasis, and poor survival. NK-NPC_II may develop from NK-NPC_I, mainly caused by an increased EBV load. Transcriptional regulation networks, protein-protein interaction networks, and competing endogenous RNA networks for each subtype of NK-NPC were constructed with each NK-NPC gene expression signature (NK-NPCGES) subtype. The results showed that the interactions among the NK-NPCGES genes were non-random; they were involved in the same molecular networks leading to the biological characteristics of the NK-NPC subtypes. The major nodes of these networks thus can be candidate treatment targets for the NK-NPC subtypes. Thioridazine, a CSCs targeting drug, was predicted to treat the two NK-NPC tumor subtypes. Conclusions NK-NPC tumors fall into two classes. Transition of NK-NPC subtypes may be associated with EBV.