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

Chen, Jiajin ; Song, Yunjie ; Li, Yi ; Wei, Yongyue ; Shen, Sipeng ; Zhao, Yang ; You, Dongfang ; Su, Li ; Bjaanæs, Maria Moksnes and Karlsson, Anna LU , et al. (2023) In Molecular Oncology 17(1). p.173-187
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
G × G interactions, NSCLC, overall survival, prognosis, trans-omics
in
Molecular Oncology
volume
17
issue
1
pages
15 pages
publisher
Elsevier
external identifiers
  • scopus:85143965681
  • pmid:36408734
ISSN
1574-7891
DOI
10.1002/1878-0261.13345
language
English
LU publication?
yes
id
cc43223f-c21f-48c0-99d6-2a06a5be2c76
date added to LUP
2023-01-27 13:57:44
date last changed
2024-06-15 02:19:26
@article{cc43223f-c21f-48c0-99d6-2a06a5be2c76,
  abstract     = {{<p>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<sub>Bonferroni</sub> ≤ 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<sub>interaction</sub> = 0.018, P = 1.87 × 10<sup>−12</sup>), which mapped to RELA × HLA-G (β<sub>interaction</sub> = 0.218, P = 8.82 × 10<sup>−11</sup>) and cg08872738 × cg27077312 (β<sub>interaction</sub> = −0.010, P = 1.16 × 10<sup>−11</sup>), which mapped to TUBA1B × TOMM40 (β<sub>interaction</sub> =−0.250, P = 3.83 × 10<sup>−10</sup>). 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.</p>}},
  author       = {{Chen, Jiajin and Song, Yunjie and Li, Yi and Wei, Yongyue and Shen, Sipeng and Zhao, Yang and You, Dongfang and Su, Li and Bjaanæs, Maria Moksnes and Karlsson, Anna and Planck, Maria and Staaf, Johan and Helland, Åslaug and Esteller, Manel and Shen, Hongbing and Christiani, David C. and Zhang, Ruyang and Chen, Feng}},
  issn         = {{1574-7891}},
  keywords     = {{G × G interactions; NSCLC; overall survival; prognosis; trans-omics}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{173--187}},
  publisher    = {{Elsevier}},
  series       = {{Molecular Oncology}},
  title        = {{A trans-omics assessment of gene–gene interaction in early-stage NSCLC}},
  url          = {{http://dx.doi.org/10.1002/1878-0261.13345}},
  doi          = {{10.1002/1878-0261.13345}},
  volume       = {{17}},
  year         = {{2023}},
}