N6-Methyladenosine Writer Gene ZC3H13 Predicts Immune Phenotype and Therapeutic Opportunities in Kidney Renal Clear Cell Carcinoma

BACKGROUND: Although the RNA modification N6-methyladenosine ZC3H13 has been found to play vital regulatory roles in many types of cancers, its role in predicting the tumor immune microenvironment (TME) and response to immune checkpoint blockade (ICB) in kidney renal clear cell carcinoma (KIRC) remains unclear. METHODS: We comprehensively analyzed the expression, prognostic significance and immunological role of ZC3H13 in pan-cancers and systematically correlated ZC3H13 with TME cell-infiltration, ICB response and targeted therapy in KIRC. The data were collected from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), Broad Institute Cancer Cell Line Encyclopedia (CCLE) and DrugBank database. Also, we performed RNA sequencing (RNA-seq) of 46 renal cell carcinoma tissues and 11 adjacent normal tissues to validate our result. All analyses were implemented using R software, version 3.6.3. RESULTS: ZC3H13 was significantly differentially expressed in most tumors. However, its expression profiles and prognostic significance were consistent only in KIRC, regardless of overall survival, progression-free survival and cancer-specific survival. Additionally, ZC3H13 expression was correlated with clinicopathological factors in KIRC. Furthermore, we found that ZC3H13 might shape a noninflamed phenotype and could predict a lower response to ICB in KIRC. These results could be validated in our own RNA-seq data. Tumor mutation burden (TMB) was significantly higher in the low ZC3H13 group. Finally, we found that ZC3H13 could predict the sensitivity of targeted therapy for KIRC. CONCLUSIONS: ZC3H13 might shape a noninflamed phenotype in KIRC. Moreover, ZC3H13 could predict the prognosis and clinical response of ICB and the sensitivity to targeted therapies in KIRC.