Genome-Wide Association Study for Searching Susceptibility Genes of Nasophargeal Carcinoma and the Interaction with Epstein-Barr Virus

Nasopharyngeal carcinoma (NPC) is a squamous cell tumor, characteristic of unique geographic and ethnic distribution. This cancer is more prominent in southeastern Asia including southern China, Hong Kong and Taiwan. In addition, NPC is closely associated with Epstein-Barr virus (EBV) infection. Thus, both genetic factors and EBV infection are considered to play a role in NPC risk. However, no genetic predictor has been systematically analyzed in NPC. In this study, two approaches: 「Genome-Wide Association (GWA)」 approach and 「Candidate Gene」 approach will be taken to search for potential genetic predictors for NPC. For the GWA approach, we plan to identify susceptibility genes of NPC by using Illumina HumanHap550 BeadChip-Duo, which covers a genome-wide scan of 550,000 tag SNPs. Two hundred cases and 200 controls matched with age and sex will be genotyped genome-wide. Additional 400 cases and 1000 controls will be collected for validation. The potential targets will be used to determine genes (SNPs) that are associated with NPC risk. These targets will also be used to evaluate its potential as a prognostic marker by using 411 patients followed up for more than 10 years in Chang Gung Memorial Hospital. Furthermore, the targets will be examined for its interactions with EBV genes that are expressed in NPC, including latent membrane protein 1 (LMP1) and EBV-encoded nuclear antigen 1 (EBNA1). For the Candidate Gene approach, we will search for potential SNPs of genes that are differentially expressed in NPC vs. adjacent normal tissues. Preliminary data indicated that one of those genes, monocyte chemoattractant protein 1 (MCP-1), which has a functional SNP at -2518, may be considered as genetic predictor for metastatic NPC (Tse et al., accepted by Clinical Cancer Research; appendex), and can be regulated by EBV LMP1 (Preliminary data). In this proposal, we plan to investigate the regulatory mechanisms of MCP-1 -2518 SNP(G/A), which are differentially activated by LMP1 and its role in NPC development. The switch between G and A resulted in changes of binding sites of potential transcription factors. Detailed analysis will be carried out to examine the role of individual transcriptional factor in MCP-1 promoter activation by LMP1 or other EBV-encoded genes. Genes identified by both approaches will be combined to evaluate the role in genetic susceptibility and in disease outcome. New findings from this study may lead to targeted therapies for NPC diagnosis, prevention and treatment.

Project ID:PA9706-1124
External Project ID:NSC97-3112-B182-008