A trans‐omics assessment of gene–gene interaction in early‐stage <scp>NSCLC</scp>

Epigenome‐wide gene–gene (G × 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 × 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 × 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 × G interactions at the gene expression level by way of a two‐phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans‐omics analysis, which had significant ( P ≤ 0.05) epigenetic cis ‐regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 ( β interaction = 0.018, P = 1.87 × 10 −12 ), which mapped to RELA × HLA‐G ( β interaction = 0.218, P = 8.82 × 10 −11 ) and cg08872738 × cg27077312 ( β interaction = −0.010, P = 1.16 × 10 −11 ), which mapped to TUBA1B × TOMM40 ( β interaction =−0.250, P = 3.83 × 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 × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.