Mol Oncol. 2022 Nov 21. doi: 10.1002/1878-0261.13345. Online ahead of print.
ABSTRACT
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 PBonferroni ≤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 (βinteraction =0.018, P=1.87×10-12 ), which mapped to RELA×HLA-G (βinteraction =0.218, P=8.82×10-11 ), and cg08872738×cg27077312 (βinteraction =-0.010, P=1.16×10-11 ), which mapped to TUBA1B×TOMM40 (βinteraction =-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.
PMID:36408734 | DOI:10.1002/1878-0261.13345
