Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 17, Issue -, Pages 362-373Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2019.05.030
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Funding
- National Key R&D Program of China [2018YFC2000100]
- National Program on Key Basic Research Project (973 Program) (973 Program) [2014CB910504]
- National Natural Science Foundation of China [61873075, 61573122]
- China Postdoctoral Science Foundation [2016M600260]
- Wu lien-teh youth science fund project of Harbin Medical University [WLD-QN1407]
- special funds for the construction of higher education in Heilongjiang Province [UNPYSCT-2016049]
- Heilongjiang Postdoctoral Foundation [LBH-Z16098]
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The accumulation of somatic driver mutations in the human genome enables cells to gradually acquire a growth advantage and contributes to tumor development. Great efforts on protein-coding cancer drivers have yielded fruitful discoveries and clinical applications. However, investigations on cancer drivers in non-coding regions, especially long non-coding RNAs (lncRNAs), are extremely scarce due to the limitation of functional understanding. Thus, to identify driver lncRNAs integrating multi-omics data in human cancers, we proposed a computational framework, DriverLncNet, which dissected the functional impact of somatic copy number alteration (CNA) of lncRNAs on regulatory networks and captured key functional effectors in dys-regulatory networks. Applying it to 5 cancer types from The Cancer Genome Atlas (TCGA), we portrayed the landscape of 117 driver lncRNAs and revealed their associated cancer hallmarks through their functional effectors. Moreover, lncRNA RP11-571M6.8 was detected to be highly associated with immunotherapeutic targets (PD-1, PD-L1, and CTLA-4) and regulatory T cell infiltration level and their markers (IL2RA and FCGR2B) in glioblastoma multiforme, highlighting its immunosuppressive function. Meanwhile, a high expression of RP11-1020A11.1 in bladder carcinoma was predictive of poor survival independent of clinical characteristics, and CTD-2256P15.2 in lung adenocarcinoma responded to the sensitivity of methyl ethyl ketone (MEK) inhibitors. In summary, this study provided a framework to decipher the mechanisms of tumorigenesis from driver lncRNA level, established a new landscape of driver lncRNAs in human cancers, and offered potential clinical implications for precision oncology.
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