Non-AIDS associated Kaposi’s sarcoma (KS) is extremely rare in the mainland Japan, but highly endemic in Okinawa, the southernmost prefecture of Japan, which consists of three major groups of islands; Okinawa main-islands, Miyako Islands and Yaeyama Islands.  Here, we aimed to elucidate the exact incidence rate and the cause of the high prevalence from both viral and human genomic aspects.
There were 60 non-AIDS associated KS cases occurred during a recent 31-year period in Okinawa Prefecture, with a population of 1.3 million. Of which 30 cases were originate from Miyako Islands, with a population of merely 57 thousands, only 4% of population of the prefecture. The incidence rates for individuals aged 50 and over were 4.6/105 per year (males: 8.3, females: 1.4) for Miyako Islands and 0.27/105 per year (males: 0.33, females: 0.21) for the rest of Okinawa.
Our survey revealed that KSHV seroprevalence was 15.4% (males: 16.6%, females: 14.1%) in Miyako Islands, about 11 times higher than those of Okinawa Islands and general population in Japan. 
Moreover, we performed whole-genome sequencing of three KSHV strains derived from patients with non-AIDS associated KS from Miyako Islands and one KSHV strain from mainland Japan. The phylogenetic tree based on the whole viral genome revealed that all four KSHV strains from the Japanese patients of non-AIDS associated KS exhibited distinct clustering from the European/US and Zambian KSHV strains.
We additionally conducted whole-exome sequencing of four male patients from Miyako Islands and examined the presence of genomic variation. However, we could not reveal any shared pathogenic mutations. 
HHV8 strains from Okinawan and Miyako Island patients with non-AIDS KS exhibited unique mutations, which are believed to contribute to the high incidence of KS in these regions.

High prevalence of originally-mutated KSHV contributes to the high incidence of non-AIDS associated Kaposi’s sarcoma in isolated Japanese islands.