Mol Oncol

Epigenome-wide gene-gene (G x G) interactions associated with non-small-cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three-step analytic strategy to identify significant and robust G x G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G x G interactions with P-Bonferroni <= 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P <= 0.05 in the validation phase. In the second step, we further performed a functional validation for these G x G interactions at the gene expression level by way of a two-phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G x G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G x G interactions using the trans-omics analysis, which had significant (P <= 0.05) epigenetic cis-regulation of transcription and robust G x G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 x cg23937960 (beta(interaction) = 0.018, P = 1.87 x 10(-12)), which mapped to RELA x HLA-G (beta(interaction) = 0.218, P = 8.82 x 10(-11)) and cg08872738 x cg27077312 (beta(interaction) = -0.010, P = 1.16 x 10(-11)), which mapped to TUBA1B x TOMM40 (beta(interaction) =-0.250, P = 3.83 x 10(-10)). A trans-omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans-omics G x G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G x G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.