Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is endemic to Guilin, China, but not Fukuoka, Japan. To examine whether the NPC in these two cities are distinct in their association with EBV, we analyzed the histology and EBV genotypes in 163 NPC from Guilin, 52 NPC from Fukuoka and non-cancerous control nasopharyngeal tissues (n=22 each) by in situ hybridization and PCR. The proportion of EBV-positive NPC from Guilin (95%) was higher than that of Fukuoka (55%, p<0.001), and higher in NPC versus control tissues in Guilin (95 vs. 46%) and Fukuoka (55 vs. 32%). Histopathologically, non-keratinizing carcinoma and the undifferentiated subtype (NKC-U) were predominant in Guilin (84%), while the proportion of keratinizing squamous cell carcinoma (KSCC, 38%) was similar to NKC-U (42%) in Fukuoka. EBV-positivity was higher in NKC-U than KSCC in the two cities. EBV genotype A was highly prevalent in Guilin and Fukuoka. However, the BamHI f variant was predominant in Guilin (79%), whereas all the identified types were the F prototype in Fukuoka. The genetic structure and biological functions of the EBV strain associated with endemic NPC in Guilin were probably different from those of Fukuoka. The genetic differences between Guilin and Fukuoka may mirror the differences in histology and patient profiles.

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