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

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Clear cell renal cell carcinoma (ccRCC) is a significant health concern with limited validated molecular targets.
• Previous m6A sequencing studies in ccRCC lack external validation, hindering clinical application.

Purpose of the Study:

• To perform external validation of previously identified m6A targets in ccRCC.
• To assess the clinical and functional impact of m6A-driven key targets on ccRCC patient survival.
• To identify reliable prognostic markers and potential therapeutic targets in ccRCC.

Main Methods:

• Utilized TCGA KIRC cohort data for expression analysis (n=530 ccRCC, n=72 normal).
• Performed external validation of 35 pre-identified m6A targets.
• Conducted overall survival (OS) analysis and gene set enrichment analyses (GSEA).

Main Results:

• Confirmed significant dysregulation of NDUFA4L2, NXPH4, SAA1, PLOD2, FCHSD1, UMOD, ANK3, CNTFR, and CHDH.
• Identified a core panel (NNU-panel: NDUFA4L2, NXPH4, UMOD) with consistent dysregulation in ccRCC.
• Strong NNU panel dysregulation correlated with significantly poorer OS (p = 0.0075).
• GSEA revealed 13 significantly upregulated gene sets associated with ccRCC progression.

Conclusions:

• External validation narrowed down dysregulated m6A targets to the NNU panel, demonstrating significant prognostic value.
• The NNU panel's dysregulation is a strong predictor of poorer overall survival in ccRCC patients.
• Epitranscriptomic modifications represent promising avenues for novel ccRCC therapies and prognostic markers.