A trans-omics assessment of gene-gene interaction in early-stage NSCLC
Chen, Jiajin (Nanjing Medical University)
Song, Yunjie (Department of Biostatistics. Nanjing Medical University)
Li, Yi (Department of Biostatistics. University of Michigan)
Wei, Yongyue (Nanjing Medical University)
Shen, Sipeng (Department of Biostatistics. Nanjing Medical University)
Zhao, Yang (Department of Biostatistics. Nanjing Medical University)
You, Dongfang (Department of Biostatistics. Nanjing Medical University)
Su, Li (Harvard Medical School)
Bjaanæs, Maria Moksnes (Department of Cancer Genetics Oslo University Hospital)
Karlsson, Anna (Department of Clinical Sciences. Lund University)
Planck, Maria (Department of Clinical Sciences. Lund University)
Staaf, Johan (Department of Clinical Sciences. Lund University)
Helland, Åslaug (Institute of Clinical Medicine. University of Oslo)
Esteller, M (Universitat de Barcelona)
Shen, Hongbing (Nanjing Medical University)
Christiani, David C. (Harvard Medical School)
Zhang, Ruyang (Nanjing Medical University)
Chen, Feng (State Key Laboratory of Reproductive Medicine. Nanjing Medical University)

Date:	2023
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 P ≤ 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 = 0. 018, P = 1. 87 × 10), which mapped to RELA × HLA-G (β = 0. 218, P = 8. 82 × 10) and cg08872738 × cg27077312 (β = −0. 010, P = 1. 16 × 10), which mapped to TUBA1B × TOMM40 (β =−0. 250, P = 3. 83 × 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.
Note:	This study was supported by the National Natural Science Foundation of China (82220108002 to FC, 82273737 to RZ, 81820108028 to HS, 81973142 to YW and 82103946 to SS), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (21KJB330004 to SS), the US National Institutes of Health (CA209414, CA249096, CA092824 and ES000002 to DCC, CA209414 and CA249096 to YL), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). RZ was partially supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	G × G interactions ; NSCLC ; Overall survival ; Prognosis ; Trans-omics
Published in:	Molecular Oncology, Vol. 17 Núm. 1 (january 2023) , p. 173-187, ISSN 1878-0261

DOI: 10.1002/1878-0261.13345
PMID: 36408734

15 p, 1.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles