Construction of Breast Cancer-Related LncSLGP Models for Systematically Deciphering Their Functions and Improving Prognosis

Abstract

With the rapid development of systematic biological approaches, researchers pay more attention to uncover the complex interplaying mechanisms of different molecular models constructed by multiple coding or non-coding RNAs in cancers, such as synthetic lethal gene pairs (SLGPs) or competing endogenous RNAs (ceRNAs). To further investigate more complex framework, we attempted to construct a LncRNA Synthetic Lethal Gene Pair (LncSLGP) model with the combination of one lncRNA and two synthetic lethal genes in health and disease conditions. We established LncSLGPs in breast cancer and expected the LncSLGPs may play more crucial roles during the development of cancers than individual RNA molecules. Through the integration of analysis of RNA-Seq, copy number variant (CNV), somatic mutation, and DNA methylation data of 411 BC samples and 83 normal samples in the TCGA database, 119 LncSLGP models containing 97 lncRNAs, 71 genes (87 SLGPs) were generated. We found the majority of lncRNAs and genes in these LncSLGP models were disease related. Function enrichment analysis showed that genes in LncSLGPs were enriched in 'IL2 STAT5 SIGNALING', 'WNT BETA-CATENIN SIGNALING', 'MYC TARGETS', and 'PI3K AKT MTOR SIGNALING' pathways. Survival analysis results of three candidate LncSLGPs, including 'LINC01133/CDC6-KRAS', 'RP11-626G11.1/KRAS-MAP3K7' and 'RP11-483H20.4/TOP1-KRAS' (log-rank pvalues: 0.002, 0.009 and 0.007, respectively) showed that they were significantly related to poor prognosis of BC patients. We developed a systematic approach to construct and identify LncSLGP models, which could be served as predictive factors for improving prognosis and guiding the clinical applications for BC patients. Funding Statement: This work was supported in part by the National Natural Science Foundation of China [Grant Nos. 31871336, 61573122, 31701159]. Wu lien-teh youth science fund project of Harbin medical university [Grant Nos. WLD-QN1407]. The Health Department Science Foundation of Heilongjiang Province (Grant Nos. 2013128), the Education Department Science Foundation of Heilongjiang Province (Grant Nos. 12541415), the Postdoctoral project of Heilongjiang Province (Grant Nos. LBH-Z14130). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Not needed.