An m6A-Driven Prognostic Marker Panel for Renal Cell Carcinoma Based on the First Transcriptome-Wide m6A-seq

Abstract

To date, only a single transcriptome-wide m6A sequencing study of clear cell renal cell carcinoma (ccRCC) has been reported, with no validation so far. Herein, by TCGA analysis of the KIRC cohort (n = 530 ccRCC; n = 72 normal), an external expression validation of 35 preidentified m6A targets was performed. Further in-depth expression stratification enabled assessment of m6A-driven key targets. Overall survival (OS) analysis and gene set enrichment analyses (GSEA) were conducted to assess their clinical and functional impact on ccRCC. In the hyper-up cluster significant upregulation was confirmed for NDUFA4L2, NXPH4, SAA1, and PLOD2 (40%) and in the hypo-up cluster for FCHSD1 (10%). Significant downregulation was observed for UMOD, ANK3, and CNTFR (27.3%) in the hypo-down cluster and for CHDH (25%) in the hyper-down cluster. In-depth expression stratification showed consistent dysregulation in ccRCC only for 11.67%: NDUFA4L2, NXPH4, and UMOD (NNU-panel). Patients with strong NNU panel dysregulation had significantly poorer OS (p = 0.0075). GSEA identified 13 associated and significantly upregulated gene sets (all p-values < 0.5; FDR < 0.25). External validation of the only available m6A sequencing in ccRCC consistently reduced dysregulated m6A-driven targets on the NNU panel with highly significant effects on OS. Epitranscriptomics are a promising target for developing novel therapies and for identifying prognostic markers for daily clinical practice.

Keywords

• epitranscriptomics
• <i>N</i>⁶-methyladenosine (m⁶A)
• METTL3
• m6A-reader
• MeRip-seq
• uromodulin