<i>Cis</i>- and <i>Trans</i>-Acting Expression Quantitative Trait Loci of Long Non-Coding RNA Impacts the Tumor Immune Microenvironment

Background: Long noncoding RNAs (lncRNAs) are implicated in various human cancers. However, the genetic regulation and clinical significance of most lncRNAs in cancers remain unknown. Method: In this study, we performed expression quantitative trait loci (eQTLs) mapping of lncRNA (elncRNA) in 11 cancer types using The Cancer Genome Atlas (TCGA) data and characterized the role of elncRNAs in the setting of genomic location, cancer association and drug sensitivity prediction. Furthermore, we performed instrumental variable (IV) analysis to dissect the downstream biological perturbation by eQTL-elncRNA pairs. Finding: 10.86% cis-eQTLs and 1.67% trans-eQTLs were related to known cancer risk-associated loci. The elncRNAs were significantly enriched in lncRNA predictors of anticancer drug sensitivity. We found that the target genes affected by eQTL-elncRNA associations are enriched in the immune system processes. We also found that eQTL-elncRNA associations can impact the fraction of immune cell types. In ovarian cancer, the rs34631313-AC092580.4 pair was shown to associate with immune-related genes (FASLG/GZMM/PYHIN1TRAT1), and with increased percentages of CD8+ T cells and M1 Macrophage. The rs9546285(13q12.3)-LINC00426 pair was shown to associate with the expression of IFNG/TNIP3/DTHD1/ZBED2 and with a higher fraction of CD8+ T cells and a lower fraction of M2 macrophages in kidney renal clear cell carcinoma. Interpretation: We revealed the genetic regulation of lncRNAs in cancers and explored the role of eQTL-elncRNA in cancer immunology. Our findings provide valuable genetic and lncRNA biomarkers for drug sensitivity and cancer immune therapy. Funding Statement:This study was supported in part by the National Natural Science Foundation of China (Grant No. 31371289 to Qiyuan Li), the Fundamental Research Funds for the Chinese Central Universities (20720190101 to Qiyuan Li), the Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 81802823 to Ying Zhou), the Natural Science Foundation of Fujian Province of China (Grant No. 2018J01054 to Ying Zhou), and the Major Project of Shanghai Science and Technology Commission of China, (Grant No. 18441901700 to Wenzhi Li). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The authors stated: Not applicable.