The Role of Critical N6-Methyladenosine-Related Long Non-Coding RNAs and Their Correlations with Immune Checkpoints in Renal Clear Cell Carcinoma.

This study aimed to evaluate the functions of critical N6-methyladenosine (m6A)-related long non-coding RNAs (lncRNAs) and their correlations with immunotherapeutic targets in clear cell renal cell carcinoma (ccRCC). m6A-related lncRNAs were analyzed using the dataset from The Cancer Genome Atlas database via Pearson correlation analysis. Then, their prognostic functions in patients with ccRCC were determined via univariate Cox analysis. A prognostic m6A-related lncRNA signature (MRLS) in ccRCC was established using the least absolute shrinkage and selection operator (LASSO) Cox regression model. In addition, the correlations between these prognostic m6A-related lncRNAs with immune checkpoints were further evaluated in clinical samples. MRLS was established by the LASSO Cox regression model on the basis of seven prognostic m6A-related lncRNAs. The risk score for each patient was calculated using the MRLS model, and the patients were further stratified into high- and low-risk subgroups. The MRLS model was validated with a robust prognostic ability by the stratification analysis. On the basis of age, grade, stage, and risk score, a nomogram was developed with a strong reliability in forecasting the overall survival percentages of the patients with ccRCC. Moreover, seven prognostic m6A-related lncRNAs enrolled in the MRLS model were found to be correlated with various immunotherapeutic targets, namely, PD-1, PD-L1, CTLA4, and LAG3, and the expression levels of which in the high-risk subgroup were significantly higher than those in the low-risk subgroup. The significant correlations between LINC00342 and the aforementioned immunotherapeutic targets were also confirmed in clinical samples. In this study, seven m6A-related lncRNAs were identified as potential biomarkers for forecasting the prognosis of patients with ccRCC and evaluating the efficacy of immunotherapy for these patients. Furthermore, a prognostic and predictive MRLS model with a high reliability was constructed to predict the overall survival probability of patients with ccRCC.

Deng W ，Wang G ，Deng H ，Yan Y ，Zhu K ，Chen R ，Liu X ，Chen L ，Zeng T ，Fu B ... -  《International Journal of General Medicine》

Integrated analysis on the N6-methyladenosine-related long noncoding RNAs prognostic signature, immune checkpoints, and immune cell infiltration in clear cell renal cell carcinoma.

Patients with advanced clear cell renal cell carcinoma (ccRCC) have a poor prognosis and lack effective prognostic biomarkers. N6-methyladenosine-related lncRNAs (m6A-related long noncoding RNAs [lncRNAs]) have been confirmed to be associated with the development of multiple tumors, but its role in ccRCC is not clear. Gene expression data and clinical information of ccRCC patients were extracted from The Cancer Genome Atlas Database. The prognostic m6A-related lncRNAs were obtained by Pearson's correlation analysis and univariate Cox regression analysis. Afterward, the cluster classification and its correlation with prognosis, clinical characteristics, and immunity were analyzed. LASSO regression was used to establish the prognostic risk model. The predictive performance of the prognostic model was evaluated and validated by survival analysis and receiver operating characteristic curve analysis, et al. The expression of immune checkpoints and immune cell infiltration in patients with different risks were systematically analyzed. A total of 27 prognostic m6A-related lncRNAs were identified. These m6A-related lncRNAs were differentially expressed between tumor and normal tissues. Among them, 24 high-risk m6A-related lncRNAs were overexpressed in Cluster 2 and correlated with poor prognosis, low stromal score, high expression of immune checkpoints, and immunosuppressive cells infiltration. Based upon, a prognostic risk model composed of seven m6A-related lncRNAs was constructed. After a series of analyses, it was proved that this model had good sensitivity and specificity, and could predict the prognosis of patients with different clinical stratification. The expression of PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, and TIGIT were significantly increased in the high-risk patients, and there was a correlation between the risk score and immune cell infiltration. The seven m6A-related lncRNAs prognostic risk signature showed reliable prognostic predictive power for ccRCC and was associated with the expression of immune checkpoints and immune cell infiltration. This seven m6A-related lncRNAs signature will be helpful in managing ccRCC and guiding individualized immunotherapy.

Qiu Y ，Wang X ，Fan Z ，Zhan S ，Jiang X ，Huang J ... -  《Immunity Inflammation and Disease》

N6-Methyladenosine-Related Long Non-coding RNA Signature Associated With Prognosis and Immunotherapeutic Efficacy of Clear-Cell Renal Cell Carcinoma.

Increasing evidence suggests that N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) play important roles in cancer progression and immunotherapeutic efficacy in clear-cell renal cell carcinoma (ccRCC). In this study, we conducted a comprehensive ccRCC RNA-seq analysis using The Cancer Genome Atlas data to establish an m6A-related lncRNA prognostic signature (m6A-RLPS) for ccRCC. Forty-four prognostic m6A-related lncRNAs (m6A-RLs) were screened using Pearson correlation analysis (|R| > 0.7, p < 0.001) and univariable Cox regression analysis (p < 0.01). Using consensus clustering, the patients were divided into two clusters with different overall survival (OS) rates and immune status according to the differential expression of the lncRNAs. Gene set enrichment analysis corroborated that the clusters were enriched in immune-related activities. Twelve prognostic m6A-RLs were selected and used to construct the m6A-RLPS through least absolute shrinkage and selection operator Cox regression. We validated the differential expression of the 12 lncRNAs between tumor and non-cancerous samples, and the expression levels of four m6A-RLs were further validated using Gene Expression Omnibus data and Lnc2Cancer 3.0 database. The m6A-RLPS was verified to be an independent and robust predictor of ccRCC prognosis using univariable and multivariable Cox regression analyses. A nomogram based on age, tumor grade, clinical stage, and m6A-RLPS was generated and showed high accuracy and reliability at predicting the OS of patients with ccRCC. The prognostic signature was found to be strongly correlated to tumor-infiltrating immune cells and immune checkpoint expression. In conclusion, we established a novel m6A-RLPS with a favorable prognostic value for patients with ccRCC. The 12 m6A-RLs included in the signature may provide new insights into the tumorigenesis and allow the prediction of the treatment response of ccRCC.

Ma T ，Wang X ，Wang J ，Liu X ，Lai S ，Zhang W ，Meng L ，Tian Z ，Zhang Y ... -  《Frontiers in Genetics》

Comprehensive Analysis of N6-Methyladenosine-Related IncRNAs Prognostic Signature and the Associated Immune Infiltrates in Kidney Renal Clear Cell Carcinoma.

Chen X ，Wang L ，Tu J ，Pan X ，Li Y ，Yin H ，Wang M ，Yuan X ... -  《CRITICAL REVIEWS IN EUKARYOTIC GENE EXPRESSION》

Prognostic Value of N6-Methyladenosine-Related lncRNAs in Early-Stage Colorectal Cancer: Association With Immune Cell Infiltration and Chemotherapeutic Drug Sensitivity.

Purpose: Accumulating evidence indicates that N6-methyladenosine-related long non-coding RNAs (m6A-related lncRNAs) play a crucial role in the occurrence and development of several cancers. We aimed to explore the potential role of m6A-related lncRNA signatures in predicting prognosis for early-stage (stages I and II) colorectal cancer (CRC). Methods: m6A-related lncRNA data were obtained from The Cancer Genome Atlas. Univariate Cox regression analysis was used to screen for prognostic m6A-related lncRNAs. Immune characteristics were analyzed in different subgroups created via unsupervised clustering analysis. Next, patients were randomly divided into training and test cohorts. In the training cohort, least absolute shrinkage and selection operator (LASSO) regression was performed to establish a prognostic model. The predictive value of the signature was evaluated in the training and test cohorts. Drug sensitivity was also examined. Results: A total of 1,478 m6A-related lncRNAs were identified. Two subgroups were created based on the expression of seven prognostic m6A-related lncRNAs. Prognosis was worse for cluster 1 than for cluster 2, and cluster 1 was characterized by increased numbers of M2 macrophages, decreased numbers of memory B cells, and higher expression of checkpoint genes when compared with cluster 2. Five m6A-related lncRNAs were selected to establish a risk prediction signature via LASSO regression. The 3 years overall survival (OS) was higher in the low-risk group than in the high-risk group. The area under the curve at 1, 2, and 3 years was 0.929, 0.954, and 0.841 in the training cohort and 0.664, 0.760, and 0.754 in the test cohort, respectively. Multivariate Cox regression analysis suggests that the risk score was an independent predictor of OS in both the training and test cohorts. A prognostic nomogram based on the five m6A-related lncRNAs and their clinical features was built and verified. The high-risk group was more sensitive to chemotherapeutic drugs (camptothecin and cisplatin) than the low-risk group. Conclusion: We identified two molecular subgroups of early-stage CRC with unique immune features based on seven prognostic m6A-related lncRNAs. Subsequent analyses demonstrated the usefulness of a five m6A-related lncRNA signature as a potential indicator of prognosis in patients with early-stage CRC.

Xiong Z ，Li X ，Yin S ，Xie M ，Mao C ，Zhang F ，Chen H ，Jin L ，Lian L ... -  《Frontiers in Molecular Biosciences》