LincSNP 3.0: an updated database for linking functional variants to human long non-coding RNAs, circular RNAs and their regulatory elements.

We describe an updated comprehensive database, LincSNP 3.0 (http://bioinfo.hrbmu.edu.cn/LincSNP), which aims to document and annotate disease or phenotype-associated variants in human long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) or their regulatory elements. LincSNP 3.0 has updated with several novel features, including (i) more types of variants including single nucleotide polymorphisms (SNPs), linkage disequilibrium SNPs (LD SNPs), somatic mutations and RNA editing sites have been expanded; (ii) more regulatory elements including transcription factor binding sites (TFBSs), enhancers, DNase I hypersensitive sites (DHSs), topologically associated domains (TADs), footprintss, methylations and open chromatin regions have been added; (iii) the associations among circRNAs, regulatory elements and variants have been identified; (iv) more experimentally supported variant-lncRNA/circRNA-disease/phenotype associations have been manually collected; (v) the sources of lncRNAs, circRNAs, SNPs, somatic mutations and RNA editing sites have been updated. Moreover, four flexible online tools including Genome Browser, Variant Mapper, Circos Plotter and Functional Annotation have been developed to retrieve, visualize and analyze the data. Collectively, LincSNP 3.0 provides associations among functional variants, regulatory elements, lncRNAs and circRNAs in diseases. It will serve as an important and continually updated resource for investigating functions and mechanisms of lncRNAs and circRNAs in diseases.

Identifying and characterizing lincRNA genomic clusters reveals its cooperative functions in human cancer.

BACKGROUND: Emerging evidence has revealed that some long intergenic non-coding RNAs (lincRNAs) are likely to form clusters on the same chromosome, and lincRNA genomic clusters might play critical roles in the pathophysiological mechanism. However, the comprehensive investigation of lincRNA clustering is rarely studied, particularly the characterization of their functional significance across different cancer types. METHODS: In this study, we firstly constructed a computational method basing a sliding window approach for systematically identifying lincRNA genomic clusters. We then dissected these lincRNA genomic clusters to identify common characteristics in cooperative expression, conservation among divergent species, targeted miRNAs, and CNV frequency. Next, we performed comprehensive analyses in differentially-expressed patterns and overall survival outcomes for patients from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) across multiple cancer types. Finally, we explored the underlying mechanisms of lincRNA genomic clusters by functional enrichment analysis, pathway analysis, and drug-target interaction. RESULTS: We identified lincRNA genomic clusters according to the algorithm. Clustering lincRNAs tended to be co-expressed, highly conserved, targeted by more miRNAs, and with similar deletion and duplication frequency, suggesting that lincRNA genomic clusters may exert their effects by acting in combination. We further systematically explored conserved and cancer-specific lincRNA genomic clusters, indicating they were involved in some important mechanisms of disease occurrence through diverse approaches. Furthermore, lincRNA genomic clusters can serve as biomarkers with potential clinical significance and involve in specific pathological processes in the development of cancer. Moreover, a lincRNA genomic cluster named Cluster127 in DLK1-DIO3 imprinted locus was discovered, which contained MEG3, MEG8, MEG9, MIR381HG, LINC02285, AL132709.5, and AL132709.1. Further analysis indicated that Cluster127 may have the potential for predicting prognosis in cancer and could play their roles by participating in the regulation of PI3K-AKT signaling pathway. CONCLUSIONS: Clarification of the lincRNA genomic clusters specific roles in human cancers could be beneficial for understanding the molecular pathogenesis of different cancer types.

MeImmS: Predict Clinical Benefit of Anti-PD-1/PD-L1 Treatments Based on DNA Methylation in Non-small Cell Lung Cancer.

Immunotherapy has become an effective therapy for cancer treatment. However, the development of biomarkers to predict immunotherapy response still remains a challenge. We have developed the DNA Methylation Immune Score, named "MeImmS," which can predict clinical benefits of non-small cell lung cancer (NSCLC) patients based on DNA methylation of 8 CpG sites. The 8 CpG sites regulate the expression of immune-related genes and MeImmS was related to immune-associated pathways, exhausted T cell markers and immune cells. Copy-number loss in 1p36.33 may affect the response of cancer patients to immunotherapy. In addition, SAA1, CXCL10, CCR5, CCL19, CXCL11, CXCL13, and CCL5 were found to be key immune regulatory genes in immunotherapy. Together, MeImmS discovered the heterogeneous of NSCLC patients and guided the immunotherapy of cancer patients in the future.

CancerClock: A DNA Methylation Age Predictor to Identify and Characterize Aging Clock in Pan-Cancer.

Many biological indicators related to chronological age have been proposed. Recent studies found that epigenetic clock or DNA methylation age is highly correlated with chronological age. In particular, a significant difference between DNA methylation age (m-age) and chronological age was observed in cancers. However, the prediction and characterization of m-age in pan-cancer remains an explored area. In this study, 1,631 age-related methylation sites in normal tissues were discovered and analyzed. A comprehensive computational model named CancerClock was constructed to predict the m-age for normal samples based on methylation levels of the extracted methylation sites. LASSO linear regression model was used to screen and train the CancerClock model in normal tissues. The accuracy of CancerClock has proved to be 81%, and the correlation value between chronological age and m-age was 0.939 (P < 0.01). Next, CancerClock was used to evaluate the difference between m-age and chronological age for 33 cancer types from TCGA. There were significant differences between predicted m-age and chronological age in large number of cancer samples. These cancer samples were defined as "age-related cancer samples" and they have some differential methylation sites. The differences between predicted m-age and chronological age may contribute to cancer development. Some of these differential methylation sites were associated with cancer survival. CancerClock provided assistance in estimating the m-age in normal and cancer samples. The changes between m-age and chronological age may improve the diagnosis and prognosis of cancers.