N6-methyladenosine methylation related immune biomarkers correlates with clinicopathological characteristics and prognosis in clear cell renal cell carcinoma.

ABSTRACT

Background: m6A modification is closely related to immune response and acts critical a role in tumor progression. In this study, we attempted to evaluate the significance of m6A in immune response and explore N6-methyladenosine (m6A) methylation-related immune biomarkers in the prognosis of clear cell renal cell carcinoma (ccRCC). Methods: The RNA-seq data and clinical phenotype of ccRCC were downloaded from The Cancer Genome Atlas (TCGA) database. Immune-related genes list was downloaded from InnateDB database. Correlation analysis, survival analysis, univariate and multivariate Cox regression analysis were used to investigate the prognostic independent m6A-related immune genes, followed by prognosis risk model establishment. Patients were divided into high/low-risk groups, followed by survival analysis, clinical factors, immune checkpoint genes and gene set variation analysis in high-risk vs. low-risk group. Results: Five prognostic independent m6A-related immune genes (PKHD1, IGF2BP3, RORA, FRK and MZF1) were identified. Low expression of PKHD1, RORA and FRK were associated with poor survival, while high expression of IGF2BP3 and MZF1 were associated with poor survival for ccRCC patients. Their expression showed correlations with multiple m6A genes. The risk model could stratify ccRCC patients into high/low risk group, and patients with high-risk were associated with short survival time. High-risk group had a high proportion of patients in tumor stage III-IV and patients with pathologic T3-T4 tumors, lymph node metastasis (N1) and distant metastasis (M1). Ten immune checkpoint genes were differentially expressed in high/low risk groups, such as PD1 and CTLA-4. The risk group could be an independent prognostic factor (HR =1.69, 95% CI 1.07-2.68, P=0.0246). Conclusions: In this study, a five-gene risk model based on m6A related immune genes was developed, which showed an independent prognostic value and was associated with tumor stage, pathologic T/N/M and immune checkpoint expression in ccRCC.