Dataset Information

Hematopoietic Gene Expression Regulation Through m6A Methylation Predicts Prognosis in Stage III Colorectal Cancer.

ABSTRACT: Background:Methylation of N6 adenosine (m6A) plays important regulatory roles in diverse biological processes. The purpose of this research was to explore the potential mechanism of m6A modification level on the clinical outcome of stage III colorectal cancer (CRC). Methods:Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were adopted to reveal the signal pathway which was most likely affected by m6A methylation. The linear models for microarray data (LIMMA) method and the least absolute shrink-age and selection operator (LASSO) Cox regression model were used to identify the signature. The signature can sensitively separate the patients into high and low risk indicating the relapse-free survival (RFS) time based on time-dependent receiver operating characteristic (ROC) analysis. Then, the multi-gene signature was validated in GSE14333 and the Cancer Genome Atlas (TCGA) cohort. The number of the samples in GSE14333 and TCGA cohort are 63 and 150. Finally, two nomograms were set up and validated to predict prognosis of patients with stage III CRC. Results:The hematopoietic cell lineage (HCL) signaling pathway was disclosed through GSEA and GSVA. Seven HCL-related genes were determined in the LASSO model to construct signature, with AUC 0.663, 0.708, and 0.703 at 1-, 3-, and 5-year RFS, respectively. Independent datasets analysis and stratification analysis indicated that the HCL-related signature was reliable in distinguishing high- and low-risk stage III CRC patients. Two nomograms incorporating the signature and pathological N stage were set up, which yielded good discrimination and calibration in the predictions of prognosis for stage III CRC patients. Conclusions:A novel HCL-related signature was developed as a predictive model for survival rate of stage III CRC patients. Nomograms based on the signature were advantageous to facilitate personalized counseling and treatment in stage III CRC.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC7556240 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Hematopoietic Gene Expression Regulation Through m<sup>6</sup>A Methylation Predicts Prognosis in Stage III Colorectal Cancer.

Zhou Zheng Z Mo Shaobo S Gu Ruiqi R Dai Weixing W Zou Xinhui X Han Lingyu L Zhang Long L Wang Renjie R Cai Guoxiang G

Frontiers in oncology 20200930

<h4>Background</h4>Methylation of N6 adenosine (m<sup>6</sup>A) plays important regulatory roles in diverse biological processes. The purpose of this research was to explore the potential mechanism of m<sup>6</sup>A modification level on the clinical outcome of stage III colorectal cancer (CRC).<h4>Methods</h4>Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were adopted to reveal the signal pathway which was most likely affected by m<sup>6</sup>A methylation. The linea ...[more]

PMID: 33102231

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Project description:BackgroundStage III colorectal cancer (CRC) patients experience varying degrees of prognosis even if receiving standard therapeutic regimes. Intravascular emboli (IVE), a type of vascular invasion, impacts the clinical outcome in CRC. In this study, we confirmed the role of IVE in predicting the prognosis of stage III CRC patients and characterized the tumor microenvironment (TME) of CRC with IVE.MethodsData from 220 consecutive patients (cohort 1) with stage III CRC undergoing radical surgery was collected retrospectively between January 2009 to December 2014. According to the presence of IVE, which was confirmed by two independent pathologists, patients were classified into two groups. Univariate and multivariate Cox regression analyses were performed to evaluate the relation of IVE presence to patients' prognosis. The association between IVE and clinicopathological factors was also analyzed. Furthermore, differentially expressed genes (DEGs) and gene set enrichment analyses (GSEA) were performed to describe features of the TME based on microarray data consisting of 6 patients. Tumor tissues from a separate cohort of 73 patients with stage III CRC (cohort 2) collected between June 2014 and December 2015 were used to analyze tumor-infiltrating lymphocyte (TIL) by immunohistochemistry (IHC) staining.ResultsIVE was observed in 126 (57.3%) patients and could serve as an unfavorable independent prognostic predictor (P < 0.001) as well as lymph node metastasis (P < 0.05) and tumor location (P < 0.05). Additionally, patients with IVE had a higher neutrophil percentage (P = 0.002) and lower lymphocyte percentage (P = 0.002) relative to those without IVE. CRC with IVE had a significantly different profile of DEGs compared to CRC without IVE, and GSEA showed chronic inflammatory and immunosuppressive TME may promote IVE development. In cohort 2, tumors with IVE had fewer CD3+ TILs in the stromal region, as well as fewer CD8+ TILs in both stromal and tumoral regions relative to those without IVE.ConclusionIVE, which was related closely to a chronic inflammatory and immunosuppressive TME, forecasted a worse prognosis of stage III CRC patients and may be taken into consideration when a therapeutic strategy is decided upon.

Project description:PurposeN6-methyladenosine (m6A) modifications represent one of the most common methylation modifications, and they are mediated by m6A RNA methylation regulators. However, their functions in renal cell carcinoma (RCC) are not completely understood. The aim of this study was to investigate the effects of the regulators in RCC.Materials and methodsThe expression levels of the 13 main m6A RNA methylation regulators in RCC were detected and consensus clustering was performed to explore their relationships with RCC. Thereafter, a risk signature based on the regulators was established. This risk model was fully verified by conducting prognostic analyses using two datasets (The Cancer Genome Atlas [TCGA] and Gene Expression Omnibus [GEO] datasets) and a ROC curve analysis.ResultsOf the 13 main m6A regulators, six were significantly upregulated and four were significantly downregulated in 893 RCC cases compared to 128 normal controls in the TCGA database. Consensus clustering based on the regulators identified two clusters of RCC cases, which were significantly associated with a pathological characteristic (T status). Thus, these results indicated that m6A RNA methylation regulators were associated with RCC. Thereafter, a risk model involving two of the regulators (METTL14 and WTAP) was established. The alterations in the mRNA and protein expression levels of these two regulators were further confirmed based on Human Protein Atlas data and real-time PCR in RCC and normal cell lines. The results indicated that the risk model may serve as an independent prognostic marker of overall survival, and it was also associated with clinicopathological characteristics (T status, M status, pathological stage, and gender) in RCC.ConclusionCollectively, the results of this study indicated that the risk model (based on two m6A RNA methylation regulators) may serve as an independent prognostic indicator of RCC, which may aid further investigation into m6A RNA modification in RCC.

Dataset Information

Hematopoietic Gene Expression Regulation Through m6A Methylation Predicts Prognosis in Stage III Colorectal Cancer.

Publications

Hematopoietic Gene Expression Regulation Through m<sup>6</sup>A Methylation Predicts Prognosis in Stage III Colorectal Cancer.

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