Identification of Five Immune-Related lncRNAs Predicting Survival and Tumor Microenvironment Characteristics in Breast Cancer.

A common cancer in females, breast cancer (BRCA) mortality has been recently reduced; however, the prognosis of BRCA patients remains poor. This study attempted to develop prognostic immune-related long noncoding RNAs (lncRNAs) for BRCA and identify the effects of these lncRNAs on the tumor microenvironment (TME). Gene expression data from The Cancer Genome Atlas (TCGA) database were collected in order to select differentially expressed lncRNAs. Immune-related lncRNAs were downloaded from the ImmLnc database, where 316 immune-related lncRNAs were identified, 12 of which were found to be significantly related to the prognosis of BRCA patients. Multivariate cox regression analysis was then applied to construct prognostic immune-related lncRNAs as the risk model, including C6orf99, LINC00987, SIAH2-AS1, LINC01010, and ELOVL2-AS1. High-risk and low-risk groups were distinguished according to the median of immune-related risk scores. Accordingly, the overall survival (OS) in the high-risk group was observed to be shorter than that in the low-risk group. qRT-PCR analysis demonstrated that lncRNA expression levels in BRCA cell lines were in basic agreement with predictions except for LINC00987. By validating numerous clinical samples, lncRNA C6orf99 was shown to be highly expressed in the advanced stage, while LINC01010 and SIAH2-AS1 decreased in the advanced T-stage and M-stage. Moreover, the expression of LINC0098 was found to be significantly decreased among the groups (>50 years old). Gene set enrichment analysis (GSEA) was applied to analyze the cancer hallmarks and immunological characteristics of the high-risk and low-risk groups. Importantly, the TIMER database demonstrated that this immune-related lncRNA risk model for breast cancer is related to the infiltration of immune cells. In conclusion, the results indicated that five immune-related lncRNAs could be used as a prognostic model and may even accelerate immunotherapy for BRCA patients.

Xiao R ，Yang M ，Tan Y ，Ding R ，Li D ... -  《-》

A prognostic model based on immune-related long noncoding RNAs for patients with epithelial ovarian cancer.

Long noncoding RNAs (lncRNAs) are important regulators of gene expression and can affect a variety of physiological processes. Recent studies have shown that immune-related lncRNAs play an important role in the tumour immune microenvironment and may have potential application value in the treatment and prognosis prediction of tumour patients. Epithelial ovarian cancer (EOC) is characterized by a high incidence and poor prognosis. However, there are few studies on immune-related lncRNAs in EOC. In this study, we focused on immune-related lncRNAs associated with survival in EOC. We downloaded mRNA data for EOC patients from The Cancer Genome Atlas (TCGA) database and mRNA data for normal ovarian tissue from the Genotype-Tissue Expression (GTEx) database and identified differentially expressed genes through differential expression analysis. Immune-related lncRNAs were obtained through intersection and coexpression analysis of differential genes and immune-related genes from the Immunology Database and Analysis Portal (ImmPort). Samples in the TCGA EOC cohort were randomly divided into a training set, validation set and combination set. In the training set, Cox regression analysis and LASSO regression were performed to construct an immune-related lncRNA signature. Kaplan-Meier survival analysis, time-dependent ROC curve analysis, Cox regression analysis and principal component analysis were performed for verification in the training set, validation set and combination set. Further studies of pathways and immune cell infiltration were conducted through Gene Set Enrichment Analysis (GSEA) and the Timer data portal. An immune-related lncRNA signature was identified in EOC, which was composed of six immune-related lncRNAs (KRT7-AS, USP30-AS1, AC011445.1, AP005205.2, DNM3OS and AC027348.1). The signature was used to divide patients into high-risk and low-risk groups. The overall survival of the high-risk group was lower than that of the low-risk group and was verified to be robust in both the validation set and the combination set. The signature was confirmed to be an independent prognostic biomarker. Principal component analysis showed the different distribution patterns of high-risk and low-risk groups. This signature may be related to immune cell infiltration (mainly macrophages) and differential expression of immune checkpoint-related molecules (PD-1, PDL1, etc.). We identified and established a prognostic signature of immune-related lncRNAs in EOC, which will be of great value in predicting the prognosis of clinical patients and may provide a new perspective for immunological research and individualized treatment in EOC.

Peng Y ，Wang H ，Huang Q ，Wu J ，Zhang M ... -  《Journal of Ovarian Research》

N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the Tumor Microenvironment and Prognostic Markers in Osteosarcoma.

N6-Adenosine methylation, yielding N6-methyladenosine (m6A), is a reversible epigenetic modification found in messenger RNAs and long non-coding RNAs (lncRNAs), which affects the fate of modified RNA molecules and is essential for the development and differentiation of immune cells in the tumor microenvironment (TME). Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents, and is characterized by high mortality. Currently, the possible role of m6A modifications in the prognosis of OS is unclear. In the present study, we investigated the correlation between m6A-related lncRNA expression and the clinical outcomes of OS patients via a comprehensive analysis. Clinical and workflow-type data were obtained from the Genotype-Tissue Expression Program and The Cancer Genome Atlas. We examined the relationship between m6A modifications and lncRNA expression, conducted Kyoto Encyclopedia of Genes analysis and also gene set enrichment analysis (GSEA), implemented survival analysis to investigate the association of clinical survival data with the expression of m6A-related lncRNAs, and utilized Lasso regression to model the prognosis of OS. Furthermore, we performed immune correlation analysis and TME differential analysis to investigate the infiltration levels of immune cells and their relationship with clinical prognosis. LncRNA expression and m6A levels were closely associated in co-expression analysis. The expression of m6A-related lncRNAs was quite low in tumor tissues; this appeared to be a predicting factor of OS in a prognostic model, independent of other clinical features. The NOD-like receptor signaling pathway was the most significantly enriched pathway in GSEA. In tumor tissues, SPAG4 was overexpressed while ZBTB32 and DEPTOR were downregulated. Tissues in cluster 2 were highly infiltrated by plasma cells. Cluster 2 presented higher ESTIMATE scores and stromal scores, showing a lower tumor cell purity in the TME. In conclusion, m6A-related lncRNA expression is strongly associated with the occurrence and development of OS, and can be used to as a prognostic factor of OS. Moreover, m6A-related lncRNAs and infiltrating immune cells in the TME could serve as new therapeutic targets and prognostic biomarkers for OS.

Wu Z ，Zhang X ，Chen D ，Li Z ，Wu X ，Wang J ，Deng Y ... -  《Frontiers in Immunology》

Oncogenic signaling pathway-related long non-coding RNAs for predicting prognosis and immunotherapy response in breast cancer.

The clinical outcomes of breast cancer (BC) are unpredictable due to the high level of heterogeneity and complex immune status of the tumor microenvironment (TME). When set up, multiple long non-coding RNA (lncRNA) signatures tended to be employed to appraise the prognosis of BC. Nevertheless, predicting immunotherapy responses in BC is still essential. LncRNAs play pivotal roles in cancer development through diverse oncogenic signal pathways. Hence, we attempted to construct an oncogenic signal pathway-based lncRNA signature for forecasting prognosis and immunotherapy response by providing reliable signatures. We preliminarily retrieved RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database and extracted lncRNA profiles by matching them with GENCODE. Following this, Gene Set Variation Analysis (GSVA) was used to identify the lncRNAs closely associated with 10 oncogenic signaling pathways from the TCGA-BRCA (breast-invasive carcinoma) cohort and was further screened by the least absolute shrinkage and selection operator Cox regression model. Next, an lncRNA signature (OncoSig) was established through the expression level of the final 29 selected lncRNAs. To examine survival differences in the stratification described by the OncoSig, the Kaplan-Meier (KM) survival curve with the log-rank test was operated on four independent cohorts (n = 936). Subsequently, multiple Cox regression was used to investigate the independence of the OncoSig as a prognostic factor. With the concordance index (C-index), the time-dependent receiver operating characteristic was employed to assess the performance of the OncoSig compared to other publicly available lncRNA signatures for BC. In addition, biological differences between the high- and low-risk groups, as portrayed by the OncoSig, were analyzed on the basis of statistical tests. Immune cell infiltration was investigated using gene set enrichment analysis (GSEA) and deconvolution tools (including CIBERSORT and ESTIMATE). The combined effect of the Oncosig and immune checkpoint genes on prognosis and immunotherapy was elucidated through the KM survival curve. Ultimately, a pan-cancer analysis was conducted to attest to the prevalence of the OncoSig. The OncoSig score stratified BC patients into high- and low-risk groups, where the latter manifested a significantly higher survival rate and immune cell infiltration when compared to the former. A multivariate analysis suggested that OncoSig is an independent prognosis predictor for BC patients. In addition, compared to the other four publicly available lncRNA signatures, OncoSig exhibited superior predictive performance (AUC = 0.787, mean C-index = 0.714). The analyses of the OncoSig and immune checkpoint genes clarified that a lower OncoSig score meant significantly longer survival and improved response to immunotherapy. In addition to BC, a high OncoSig score in several other cancers was negatively correlated with survival and immune cell infiltration. Our study established a trustworthy and discriminable prognostic signature for BC patients with similar clinical profiles, thus providing a new perspective in the evaluation of immunotherapy responses. More importantly, this finding can be generalized to be applicable to the vast majority of human cancers.

Li H ，Liu H ，Hao Q ，Liu X ，Yao Y ，Cao M ... -  《Frontiers in Immunology》

Bioinformatics profiling utilized a nine immune-related long noncoding RNA signature as a prognostic target for pancreatic cancer.

To identify an immune-related long noncoding RNA (lncRNA) signature with potential prognostic value for patients with pancreatic cancer. Pancreatic cancer samples with available clinical information and whole genomic mRNA expression data obtained from The Cancer Genome Atlas (TCGA) were enrolled in our research. The immune score of each sample was calculated according to the expression level of immune-related genes and used to identify the most promising immune-related lncRNAs. According to the risk score developed from screened immune-related lncRNAs, the high- and low-risk groups were separated on the basis of the median risk score. The prediction reliability was further evaluated in the validation set and combination set. Both gene set enrichment analysis (GSEA) and principal component analysis (PCA) were performed for functional annotation, and the microenvironment cell population record was applied to evaluate the immune composition and purity of the tumor. A cohort of 176 samples was included in this study. A total of 163 immune-related lncRNAs were collected according to Pearson correlation analyses between immune score and lncRNA expression |R| > 0.5, P < 0.01). Nine immune-related lncRNAs (AL138966.2, AL133520.1, AC142472.1, AC127024.5, AC116913.1, AC083880.1, AC124016.1, AC008443.5, and AC092171.5) with the most significant prognostic values (P < 0.01) were identified. In the training set, it was observed that patients in the low-risk group showed longer overall survival (OS) than those in the high-risk group (P < 0.001); meanwhile, similar results were found in the validation set, combination set and various stratified sets (P < 0.05, P < 0.001, P < 0.05, respectively). Moreover, the signature was identified as an independent prognostic factor and significantly associated with the OS of pancreatic cancer. The area under curve (AUC) of the receiver operating characteristic curve (ROC curve) for the nine lncRNA signature in predicting the 2-year survival rate was 0.703. In addition, the low-risk and high-risk groups displayed different distributed patterns in PCA and different immune statuses in the GSEA. The signature indicated decreased purity of the tumor by implying a lower proportion of cancer cells along with an increasing enrichment of fibroblasts, myeloid dendritic cells, and monocytic lineage cells. Our research suggests that the immune-related lncRNA signature possesses latent prognostic value for patients with pancreatic cancer and may provide new information for immunological research and treatment in pancreatic cancer.

Wei C ，Liang Q ，Li X ，Li H ，Liu Y ，Huang X ，Chen X ，Guo Y ，Li J ... -  《-》