Synergistic triad epistasis of epigenetic H3K27me modifier genes, EZH2, KDM6A, and KDM6B, in gastric cancer susceptibility

For an epigenetic regulation of human genome, three enzymes write or erase methylation of lysine-27 residue on histone H3 (H3K27me). This methylation is catalyzed by EZH2 (KMT6A) methyltransferase and reversed by KDM6A (UTX) or KDM6B (JMJD3) demethylase. Genetic cancer risk association has been reported on EZH2, but not on KDM6A or KDM6B yet. A total of 23 tag single-nucleotide polymorphisms (SNPs) of the three genes were genotyped in 2349 Korean participants, and their gastric cancer risk associations and epistases were statistically examined by comparing the SNP genotypes of 1100 gastric cancer patients and 1249 healthy controls. All three genes are individually associated with gastric cancer susceptibility, as evident with the genotypes of KDM6A SNP rs5952279 (P = 0.00010) and rs144974719 (P = 0.00024), KDM6B rs78633955 (P = 0.0019) and rs11657063 (P = 0.0036), and EZH2 rs67648693 (P = 0.0028) and rs1061037 (P = 0.023). Furthermore, when odds ratio of interaction (ORint) is calculated for all intergenic SNP pairs, synergistic epistasis is evident among the three genes. Specifically, the interaction is synergistic between EZH2 rs58579167 and KDM6A rs5952279 (ORint = 3.2, P = 0.00066), between KDM6A rs2230018 and KDM6B rs78633955 (ORint = 1.9, P = 0.044), and between KDM6B rs78633955 and EZH2 rs73158295 (ORint = 1.7, P = 0.00030). These inter-SNP interactions together constitute a synergistic triad epistasis of ring-type topology. All three H3K27me modifier genes are individually associated with gastric cancer susceptibility with synergistic triad interaction. Not only two enzymes with the same function (KDM6A and KDM6B), but also those with opposite functions (EZH2 versus KDM6A or KDM6B) synergistically affect H3K27me consequences such as gastric cancer susceptibility.