A trans‐omics assessment of gene–gene interaction in early‐stage NSCLC

• Published in: Molecular oncology Vol. 17; no. 1; pp. 173 - 187
• Main Authors: Chen, Jiajin, Song, Yunjie, Li, Yi, Wei, Yongyue, Shen, Sipeng, Zhao, Yang, You, Dongfang, Su, Li, Bjaanæs, Maria Moksnes, Karlsson, Anna, Planck, Maria, Staaf, Johan, Helland, Åslaug, Esteller, Manel, Shen, Hongbing, Christiani, David C., Zhang, Ruyang, Chen, Feng
• Format: Journal Article
• Language: English; Norwegian
• Published: United States John Wiley & Sons, Inc 01.01.2023; John Wiley and Sons Inc; Wiley
• Subjects: Analysis; Biomedical research; Biotechnology industry; Cancer and Oncology; Cancer och onkologi; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell survival; Clinical Medicine; Collaboration; Disease; DNA methylation; DNA Methylation - genetics; DNA probes; Epigenetic inheritance; Epigenetics; Epigenome; G × G interactions; Gene expression; Gene regulation; Genomes; Health aspects; Hospitals; Humans; International economic relations; Klinisk medicin; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - metabolism; Mediation; Medical and Health Sciences; Medical prognosis; Medical research; Medicin och hälsovetenskap; Methylation; Molecular modelling; Non-small cell lung carcinoma; NSCLC; overall survival; prognosis; Quality control; Review boards; Small Cell Lung Carcinoma - genetics; Statistical analysis; Therapeutic targets; trans-omics; Transcription; Transcriptomics; Tumors; United States; Sweden; United States > US; Norway; Massachusetts; Spain; overall survival; NSCLC; trans-omics; prognosis; G × G interactions
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13345

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. A three‐step, trans‐omics study identified two gene–gene interactions, cg14391855 × cg23937960 (mapped to RELA × HLA‐G) as well as cg08872738 × cg27077312 (mapped to TUBA1B × TOMM40), which were significantly and robustly associated with NSCLC survival at both the epigenetic and transcriptional levels. Our findings have implications of precision treatment by providing therapeutic targets for early‐stage NSCLC patients.